HUMANIZED ANTIBODIES WITH ULTRALONG COMPLEMENTARY DETERMINING REGIONS

• US 20160159928A1
• Filed: 07/18/2014
• Published: 06/09/2016
• Est. Priority Date: 07/18/2013
• Status: Active Grant

• Current Assignee: Taurus Biosciences LLC (Ligand Pharmaceuticals, Inc.)
• Original Assignee: Fabrus, LLC. (Eloxx Pharmaceuticals, Inc.)
• Inventors: Bazirgan, Omar, de los Rios, Miguel
• Granted Patent: US 10,640,574 B2
• Time in Patent Office: Days
• CPC Class Codes: C07K 14/43504 from invertebrates
• CPC Class Codes: C07K 14/43522 from scorpions
• CPC Class Codes: C07K 14/522 Alpha-chemokines, e.g. NAP-2, ENA-78, GRO-alpha/MGSA/NAP-3, GRO-beta/MIP-2alpha, GRO-gamma/MIP-2beta, IP-10, GCP-2, MIG, PBSF, PF-4, KC
• CPC Class Codes: C07K 14/54 Interleukins [IL]
• CPC Class Codes: C07K 14/5421 IL-8
• CPC Class Codes: C07K 14/655 Somatostatins
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/005 constructed by phage libraries
• CPC Class Codes: C07K 16/1081 Togaviridae, e.g. flavivirus, rubella virus, hog cholera virus
• CPC Class Codes: C07K 16/464 Igs containing CDR-residues from one specie grafted between FR-residues from another
• CPC Class Codes: C07K 2317/20 characterized by taxonomic origin
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2318/10 Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C40B 40/10 Libraries containing peptides or polypeptides, or derivatives thereof

Abstract

The present disclosure provides humanized antibodies, including antibodies comprising an ultralong CDR3 and uses thereof.

Claims

1. A humanized antibody or binding fragment thereof comprising a heavy chain variable region comprising:

(a) an amino acid sequence selected from the group consisting of;

(i) SEQ ID NO;

734 or SEQ ID NO;

735,

(ii) SEQ ID NO;

736 or SEQ ID NO;

737,

(iii) SEQ ID NO;

738 or SEQ ID NO;

739,

(iv) SEQ ID NO;

740 or SEQ ID NO;

741,

(v) SEQ ID NO;

742 or SEQ ID NO;

743,

(vi) SEQ ID NO;

744 or SEQ ID NO;

745,

(vii) SEQ ID NO;

746 or SEQ ID NO 747, and

(viii) SEQ ID NO;

748 or SEQ ID NO;

749; and

(b) an ultralong CDR3.

2. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 is 35 amino acids in length or longer, 40 amino acids in length or longer, 45 amino acids in length or longer, 50 amino acids in length or longer, 55 amino acids in length or longer, or 60 amino acids in length or longer.

3. The humanized antibody or binding fragment thereof of claim 2, wherein the ultralong CDR3 is 35 amino acids in length or longer.

4. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises 3 or more cysteine residues, 4 or more cysteine residues, 5 or more cysteine residues, 6 or more cysteine residues, 7 or more cysteine residues, 8 or more cysteine residues, 9 or more cysteine residues, 10 or more cysteine residues, 11 or more cysteine residues, or 12 or more cysteine residues.

5. The humanized antibody or binding fragment thereof of claim 4, wherein the ultralong CDR3 comprises 3 or more cysteine residues.

6. The humanized antibody or binding fragment thereof of claim 1, wherein the antibodies or binding fragments thereof comprise a cysteine motif.

7. The humanized antibody or binding fragment thereof of claim 6, wherein the cysteine motif is selected from the group consisting of:

CX₁₀CX₅CX₅CXCX₇C (SEQ ID NO;

     41), CX₁₀CX₆CX₅CXCX₁₅C (SEQ ID NO;

     42), CX₁₁CXCX₅C (SEQ ID NO;

     43), CX₁₁CX₅CX₅CXCX₇C (SEQ ID NO;

     44), CX₁₀CX₆CX₅CXCX₁₃C (SEQ ID NO;

     45), CX₁₀CX₅CXCX₄CX₈C (SEQ ID NO;

     46), CX₁₀CX₆CX₆CXCX₇C (SEQ ID NO;

     47), CX₁₀CX₄CX₇CXCX₈C (SEQ ID NO;

     48), CX₁₀CX₄CX₇CXCX₇C (SEQ ID NO;

     49), CX₁₃CX₈CX₈C (SEQ ID NO;

     50), CX₁₀CX₆CX₅CXCX₇C (SEQ ID NO;

     51), CX₁₀CX₅CX₅C (SEQ ID NO;

     52), CX₁₀CX₅CX₆CXCX₇C (SEQ ID NO;

     53), CX₁₀CX₆CX₅CX₇CX₉C (SEQ ID NO;

     54), CX₉CX₇CX₅CXCX₇C (SEQ ID NO;

     55), CX₁₀CX₆CX₅CXCX₉C (SEQ ID NO;

     56), CX₁₀CXCX₄CX₅CX₁₁C (SEQ ID NO;

     57), CX₇CX₃CX₆CX₅CXCX₅CX₁₀C (SEQ ID NO;

     58), CX₁₀CXCX₄CX₅CXCX₂CX₃C (SEQ ID NO;

     59), CX₁₆CX₅CXC (SEQ ID NO;

     60), CX₆CX₄CXCX₄CX₅C (SEQ ID NO;

     61), CX₁₁CX₄CX₅CX₆CX₃C (SEQ ID NO;

     62), CX₈CX₂CX₆CX₅C (SEQ ID NO;

     63), CX₁₀CX₅CX₅CXCX₁₀C (SEQ ID NO;

     64), CX₁₀CXCX₆CX₄CXC (SEQ ID NO;

     65), CX₁₀CX₅CX₅CXCX₂C (SEQ ID NO;

     66), CX₁₄CX₂CX₃CXCXC (SEQ ID NO;

     67), CX₁₅CX₅CXC (SEQ ID NO;

     68), CX₄CX₆CX₉CX₂CX₁₁C (SEQ ID NO;

     69), CX₆CX₄CX₅CX₅CX₁₂C (SEQ ID NO;

     70), CX₇CX₃CXCXCX₄CX₅CX₉C (SEQ ID NO;

     71), CX₁₀CX₆CX₅C (SEQ ID NO;

     72), CX₇CX₃CX₅CX₅CX₉C (SEQ ID NO;

     73), CX₇CX₅CXCX₂C (SEQ ID NO;

     74), CX₁₀CXCX₆C (SEQ ID NO;

     75), CX₁₀CX₃CX₃CX₅CX₇CXCX₆C (SEQ ID NO;

     76), CX₁₀CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     77), CX₁₂CX₄CX₅CXCXCX₉CX₃C (SEQ ID NO;

     78), CX₁₂CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     79), CX₁₀CX₆CX₅CXCX₁₁C (SEQ ID NO;

     80), CX₁₆CX₅CXCXCX₁₄C (SEQ ID NO;

     81), CX₁₀CX₅CXCX₈CX₆C (SEQ ID NO;

     82), CX₁₂CX₄CX₅CX₈CX₂C (SEQ ID NO;

     83), CX₁₂CX₅CX₅CXCX₈C (SEQ ID NO;

     84), CX₁₀CX₆CX₅CXCX₄CXCX₉C (SEQ ID NO;

     85), CX₁₁CX₄CX₅CX₈CX₂C (SEQ ID NO;

     86), CX₁₀CX₆CX₅CX₈CX₂C (SEQ ID NO;

     87), CX₁₀CX₆CX₅CXCX₈C (SEQ ID NO;

     88), CX₁₀CX₆CX₅CXCX₃CX₈CX₂C (SEQ ID NO;

     89), CX₁₀CX₆CX₅CX₃CX₈C (SEQ ID NO;

     90), CX₁₀CX₆CX₅CXCX₂CX₆CX₅C (SEQ ID NO;

     91), CX₇CX₆CX₃CX₃CX₉C (SEQ ID NO;

     92), CX₉CX₈CX₅CX₆CX₅C (SEQ ID NO;

     93), CX₁₀CX₂CX₂CX₇CXCX₁₁CX₅C (SEQ ID NO;

     94), and CX₁₀CX₆CX₅CXCX₂CX₈CX₄C (SEQ ID NO;

     95).

8. The humanized antibody or binding fragment thereof of claim 6, wherein the cysteine motif is selected from the group consisting of:

CCX₃CXCX₃CX₂CCXCX₅CX₉CX₅CXC (SEQ ID NO;

     96), CX₆CX₂CX₅CX₄CCXCX₄CX₆CXC (SEQ ID NO;

     97), CX₇CXCX₅CX₄CCCX₄CX₆CXC (SEQ ID NO;

     98), CX₉CX₃CXCX₂CXCCCX₆CX₄C (SEQ ID NO;

     99), CX₅CX₃CXCX₄CX₄CCX₁₀CX₂CC (SEQ ID NO;

     100), CX₅CXCX₁CXCX₃CCX₃CX₄CX₁₀C (SEQ ID NO;

     101), CX₉CCCX₃CX₄CCCX₅CX₆C (SEQ ID NO;

     102), CCX₈CX₅CX₄CX₃CX₄CCXCX₁C (SEQ ID NO;

     103), CCX₆CCX₅CCCX₄CX₄CX₁₂C (SEQ ID NO;

     104), CX₆CX₂CX₃CCCX₄CX₅CX₃CX₃C (SEQ ID NO;

     105), CX₃CX₅CX₆CX₄CCXCX₅CX₄CXC (SEQ ID NO;

     106), CX₄CX₄CCX₄CX₄CXCX₁₁CX₂CXC (SEQ ID NO;

     107), CX₅CX₂CCX₅CX₄CCX₃CCX₇C (SEQ ID NO;

     108), CX₅CX₅CX₃CX₂CXCCX₄CX₇CXC (SEQ ID NO;

     109), CX₃CX₇CX₃CX₄CCXCX₂CX₅CX₂C (SEQ ID NO;

     110), CX₉CX₃CXCX₄CCX₅CCCX₆C (SEQ ID NO;

     111), CX₉CX₃CXCX₂CXCCX₆CX₃CX₃C (SEQ ID NO;

     112), CX₈CCXCX₃CCX₃CXCX₃CX₄C (SEQ ID NO;

     113), CX₉CCX₄CX₂CXCCXCX₄CX₃C (SEQ ID NO;

     114), CX₁₀CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     115), CX₉CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     116), CX₆CCXCX₅CX₄CCXCX₅CX₂C (SEQ ID NO;

     117), CX₆CCXCX₃CXCCX₃CX₄CC (SEQ ID NO;

     118), CX₆CCXCX₃CXCX₂CXCX₄CX₈C (SEQ ID NO;

     119), CX₄CX₂CCX₃CXCX₄CCX₂CX₃C (SEQ ID NO;

     120), CX₃CX₅CX₃CCCX₄CX₉C (SEQ ID NO;

     121), CCX₉CX₃CXCCX₃CX₅C (SEQ ID NO;

     122), CX₉CX₂CX₃CX₄CCX₄CX₅C (SEQ ID NO;

     123), CX₉CX₇CX₄CCXCX₇CX₃C (SEQ ID NO;

     124), CX₉CX₃CCCX₁₀CX₂CX₃C (SEQ ID NO;

     125), CX₃CX₅CX₅CX₄CCX₁₀CX₆C (SEQ ID NO;

     126), CX₉CX₅CX₄CCXCX₅CX₄C (SEQ ID NO;

     127), CX₇CXCX₆CX₄CCCX₁₀C (SEQ ID NO;

     128), CX₈CX₂CX₄CCX₄CX₃CX₃C (SEQ ID NO;

     129), CX₇CX₅CXCX₄CCX₇CX₄C (SEQ ID NO;

     130), CX₁₁CX₃CX₄CCCX₈CX₂C (SEQ ID NO;

     131), CX₂CX₃CX₄CCX₄CX₅CX₁₅C (SEQ ID NO;

     132), CX₉CX₅CX₄CCX₇C (SEQ ID NO;

     133), CX₉CX₇CX₃CX₂CX₆C (SEQ ID NO;

     134), CX₉CX₅CX₄CCX₁₄C (SEQ ID NO;

     135), CX₉CX₅CX₄CCX₈C (SEQ ID NO;

     136), CX₉CX₆CX₄CCXC (SEQ ID NO;

     137), CX₅CCX₇CX₄CX₁₂ (SEQ ID NO;

     138), CX₁₀CX₃CX₄CCX₄C (SEQ ID NO;

     139), CX₉CX₄CCX₅CX₄C (SEQ ID NO;

     140), CX₁₀CX₃CX₄CX₇CXC (SEQ ID NO;

     141), CX₇CX₇CX₂CX₂CX₃C (SEQ ID NO;

     142), CX₉CX₄CX₄CCX₆C (SEQ ID NO;

     143), CX₇CXCX₃CXCX₆C (SEQ ID NO;

     144), CX₇CXCX₄CXCX₄C (SEQ ID NO;

     145), CX₉CX₅CX₄C (SEQ ID NO;

     146), CX₃CX₆CX₈C (SEQ ID NO;

     147), CX₁₀CXCX₄C (SEQ ID NO;

     148), CX₁₀CCX₄C (SEQ ID NO;

     149), CX₁₅C (SEQ ID NO;

     150), CX₁₀C (SEQ ID NO;

     151), and CX₉C (SEQ ID NO;

     152).

9. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises 2 to 6 disulfide bonds.

10. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises SEQ ID NO:

40 or a derivative thereof.

11. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises amino acid residues 3-6 of any of one SEQ ID NO:

1-4.

12. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises a non-human DH or a derivative thereof.

13. The humanized antibody or binding fragment thereof of claim 12, wherein the non-human DH is SEQ ID NO:

5, SEQ ID NO;

6, SEQ ID NO;

7, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, or SEQ ID NO;

12.

14. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises a JH sequence or a derivative thereof.

15. The humanized antibody or binding fragment thereof of claim 14, wherein the JH sequence comprises amino acids at positions 5-15 of SEQ ID NO:

13, SEQ ID NO;

14, SEQ ID NO;

15, SEQ ID NO;

16, or SEQ ID NO;

17.

16. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises:

a sequence derived from a non-human VH sequence or a derivative thereof;

a sequence derived from a non-human DH sequence or a derivative thereof; and

/or

a sequence derived from a JH sequence or derivative thereof.

17. The humanized antibody or binding fragment thereof of claim 16, wherein the ultralong CDR3 comprises an additional amino acid sequence comprising two to six amino acid residues or more positioned between the VH sequence and the DH sequence.

18. The humanized antibody or binding fragment thereof of claim 17, wherein the additional amino acid sequence is selected from the group consisting of:

IR, IF, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

20 or SEQ ID NO;

21.

19. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises a sequence derived from or based on SEQ ID NO:

22, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, or SEQ ID NO;

28.

20. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises a non-bovine sequence or a non-antibody sequence.

21. The humanized antibody or binding fragment thereof of claim 20, wherein the non-antibody sequence is a synthetic sequence.

22. The humanized antibody or binding fragment thereof of claim 20, wherein the non-antibody sequence is a cytokine sequence, a lymphokine sequence, a chemokine sequence, a growth factor sequence, a hormone sequence, or a toxin sequence.

23. The humanized antibody or binding fragment thereof of claim 20, wherein the non-antibody sequence is an IL-8 sequence, an IL-21 sequence, an SDF-1 (alpha) sequence, a somatostatin sequence, a chlorotoxin sequence, a Pro-TxII sequence, a ziconotide sequence, an ADWX-1 sequence, an HsTx1 sequence, an OSK1 sequence, a Pi2 sequence, a Hongotoxin (HgTX) sequence, a Margatoxin sequence, an Agitoxin-2 sequence, a Pi3 sequence, a Kaliotoxin sequence, an Anuroctoxin sequence, a Charybdotoxin sequence, a Tityustoxin -K- alpha sequence, a Maurotoxin sequence, a Ceratotoxin 1 (CcoTx1) sequence, a CcoTx2 sequence, a CcoTx3 sequence, a Phrixotoxin 3 (PaurTx3) sequence, a Hanatoxin 1 sequence, a Phrixotoxin 1 sequence, a Huwentoxin-IV sequence, an α

-conotoxin ImI sequence, an α

-conotoxin EpI sequence, an α

-conotoxin PnIA sequence, an α

-conotoxin PnIB sequence, an α

-conotoxin MII sequence, an α

-conotoxin AuIA sequence, an α

-conotoxin AuIB sequence, an α

-conotoxin AuIC sequence, a conotoxin κ

-PVIIA sequence, a charybdotoxin sequence, a neurotoxin B-IV sequence, a crotamine sequence, a ω

-GVIA (conotoxin) sequence, a κ

-hefutoxin 1 sequence, a Css4 sequence, a Bj-xtrIT sequence, a BcIV sequence, a Hm-1 sequence, a Hm-2 sequence, a GsAF-I (β

-theraphotoxin-Gr1b) sequence, a Protoxin I (ProTx-I sequence, a β

-theraphotoxin-Tp1a) sequence, a Protoxin II (ProTx II) sequence, a Huwentoxin I sequence, a μ

-Conotoxin PIIIA sequence, a Jingzhaotoxin-III (β

-TRTX-Cj1a) sequence, a GsAF-II (Kappa-theraphotoxin-Gr2c) sequence, a ShK (Stichodactyla toxin) sequence, a HsTx1 sequence, a Guangxitoxin 1E (GxTx-1E) sequence, a Maurotoxin sequence, a Charybdotoxin (ChTX) sequence, an Iberiotoxin (IbTx) sequence, a Leiurotoxin 1 (scyllatoxin) sequence, a Tamapin sequence, a Kaliotoxin-1 (KTX) sequence, a Purotoxin1 (PT-1) sequence, or a GpTx-1 sequence, a MOKA Toxin sequence, a OSK1 (P12, K16, D20) sequence, a OSK1 (K16, D20) sequence, a HmK sequence, a ShK (K16, Y26, K29) sequence, a ShK (K16) sequence, a ShK-A (K16) sequence, a ShK (K16, E30) sequence, a ShK (Q21) sequence, a ShK (L21) sequence, a ShK (F21) sequence, a ShK (121) sequence, or a ShK (A21) sequence.

24. The humanized antibody or binding fragment thereof of claim 20, wherein the non-antibody sequence is any one of SEQ ID NOS:

475-481, 599-655, 666-698, 727-733, 808-810, and 831-835.

25. The humanized antibody or binding fragment thereof of claim 20, wherein the antibody heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

770-779, 784-791, 903-922 and 925-955.

26. The humanized antibody or binding fragment thereof of claim 20, wherein the humanized antibody or binding fragment thereof comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO:

956 or 959.

27. The humanized antibody or binding fragment thereof of claim 20, wherein the antibody heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

770-779, 784-791, 903-922 and 925-955, and wherein the humanized antibody or binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO;

959.

28. The humanized antibody or binding fragment thereof of claim 20, wherein the antibody heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

941, and wherein the humanized antibody or binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO;

959.

29. The humanized antibody or binding fragment thereof of claim 20, wherein the antibody heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

770-779, 784-791, 903-922 and 925-955, and wherein the humanized antibody or binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO;

956.

30. The humanized antibody or binding fragment thereof of claim 20, wherein the non-antibody sequence replaces at least a portion of the ultralong CDR3.

31. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵ motif,

wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q).

32. The humanized antibody or binding fragment thereof of claim 31, wherein the X¹X²X³X⁴X⁵ motif is TTVHQ (SEQ ID NO:

153), TSVHQ (SEQ ID NO;

     154), SSVTQ (SEQ ID NO;

     155), STVHQ (SEQ ID NO;

     156), ATVRQ (SEQ ID NO;

     157), TTVYQ (SEQ ID NO;

     158), SPVHQ (SEQ ID NO;

     159), ATVYQ (SEQ ID NO;

     160), TAVYQ (SEQ ID NO;

     161), TNVHQ (SEQ ID NO;

     162), ATVHQ (SEQ ID NO;

     163), STVYQ (SEQ ID NO;

     164), TIVHQ (SEQ ID NO;

     165), AIVYQ (SEQ ID NO;

     166), TTVFQ (SEQ ID NO;

     167), AAVFQ (SEQ ID NO;

     168), GTVHQ (SEQ ID NO;

     169), ASVHQ (SEQ ID NO;

     170), TAVFQ (SEQ ID NO;

     171), ATVFQ (SEQ ID NO;

     172), AAAHQ (SEQ ID NO;

     173), VWYQ (SEQ ID NO;

     174), GTVFQ (SEQ ID NO;

     175), TAVHQ (SEQ ID NO;

     176), ITVHQ (SEQ ID NO;

     177), ITAHQ (SEQ ID NO;

     178), VTVHQ (SEQ ID NO;

     179);

AAVHQ (SEQ ID NO;

     180), GTVYQ (SEQ ID NO;

     181), TTVLQ (SEQ ID NO;

     182), TTTHQ (SEQ ID NO;

     183), or TTDYQ (SEQ ID NO;

     184).

33. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises a CX¹X²X³X⁴X⁵ motif.

34. The humanized antibody or binding fragment thereof of claim 33, wherein the CX¹X²X³X⁴X⁵ motif is CTTVHQ (SEQ ID NO:

185), CTSVHQ (SEQ ID NO;

     186), CSSVTQ (SEQ ID NO;

     187), CSTVHQ (SEQ ID NO;

     188), CATVRQ (SEQ ID NO;

     189), CTTVYQ (SEQ ID NO;

     190), CSPVHQ (SEQ ID NO;

     191), CATVYQ (SEQ ID NO;

     192), CTAVYQ (SEQ ID NO;

     193), CTNVHQ (SEQ ID NO;

     194), CATVHQ (SEQ ID NO;

     195), CSTVYQ (SEQ ID NO;

     196), CTIVHQ (SEQ ID NO;

     197), CAIVYQ (SEQ ID NO;

     198), CTTVFQ (SEQ ID NO;

     199), CAAVFQ (SEQ ID NO;

     200), CGTVHQ (SEQ ID NO;

     201), CASVHQ (SEQ ID NO;

     202), CTAVFQ (SEQ ID NO;

     203), CATVFQ (SEQ ID NO;

     204), CAAAHQ (SEQ ID NO;

     205), CVVVYQ (SEQ ID NO;

     206), CGTVFQ (SEQ ID NO;

     207), CTAVHQ (SEQ ID NO;

     208), CITVHQ (SEQ ID NO;

     209), CITAHQ (SEQ ID NO;

     210), CVTVHQ (SEQ ID NO;

     211);

CAAVHQ (SEQ ID NO;

     212), CGTVYQ (SEQ ID NO;

     213), CTTVLQ (SEQ ID NO;

     214), CTTTHQ (SEQ ID NO;

     215), or CTTDYQ (SEQ ID NO;

     216).

35. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises a (X^aX^b)_z motif,

wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein z is 1-4.

36. The humanized antibody or binding fragment thereof of claim 35, wherein the (X^aX^b)_z motif is CYTYNYEF (SEQ ID NO:

217), HYTYTYDF (SEQ ID NO;

     218), HYTYTYEW (SEQ ID NO;

     219), KHRYTYEW (SEQ ID NO;

     220), NYIYKYSF (SEQ ID NO;

     221), PYIYTYQF (SEQ ID NO;

     222), SFTYTYEW (SEQ ID NO;

     223), SYIYIYQW (SEQ ID NO;

     224), SYNYTYSW (SEQ ID NO;

     225), SYSYSYEY (SEQ ID NO;

     226), SYTYNYDF (SEQ ID NO;

     227), SYTYNYEW (SEQ ID NO;

     228), SYTYNYQF (SEQ ID NO;

     229), SYVWTHNF (SEQ ID NO;

     230), TYKYVYEW (SEQ ID NO;

     231), TYTYTYEF (SEQ ID NO;

     232), TYTYTYEW (SEQ ID NO;

     233), VFTYTYEF (SEQ ID NO;

     234), AYTYEW (SEQ ID NO;

     235), DYIYTY (SEQ ID NO;

     236), IHSYEF (SEQ ID NO;

     237), SFTYEF (SEQ ID NO;

     238), SHSYEF (SEQ ID NO;

     239), THTYEF (SEQ ID NO;

     240), TWTYEF (SEQ ID NO;

     241), TYNYEW (SEQ ID NO;

     242), TYSYEF (SEQ ID NO;

     243), TYSYEH (SEQ ID NO;

     244), TYTYDF (SEQ ID NO;

     245), TYTYEF (SEQ ID NO;

     246), TYTYEW (SEQ ID NO;

     247), AYEF (SEQ ID NO;

     248), AYSF (SEQ ID NO;

     249), AYSY (SEQ ID NO;

     250), CYSF (SEQ ID NO;

     251), DYTY (SEQ ID NO;

     252), KYEH (SEQ ID NO;

     253), KYEW (SEQ ID NO;

     254), MYEF (SEQ ID NO;

     255), NWIY (SEQ ID NO;

     256), NYDY (SEQ ID NO;

     257), NYQW (SEQ ID NO;

     258), NYSF (SEQ ID NO;

     259), PYEW (SEQ ID NO;

     260), RYNW (SEQ ID NO;

     261), RYTY (SEQ ID NO;

     262), SYEF (SEQ ID NO;

     263), SYEH (SEQ ID NO;

     264), SYEW (SEQ ID NO;

     265), SYKW (SEQ ID NO;

     266), SYTY (SEQ ID NO;

     267), TYDF (SEQ ID NO;

     268), TYEF (SEQ ID NO;

     269), TYEW (SEQ ID NO;

     270), TYQW (SEQ ID NO;

     271), TYTY (SEQ ID NO;

     272), or VYEW (SEQ ID NO;

     273).

37. The humanized antibody or binding fragment thereof of claim 35, wherein the (X^aX^b)_z motif is YXYXYX.

38. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵X_n motif,

wherein X₁ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X₂ is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X₃ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X₄ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), wherein X₅ is glutamine (Q), and wherein n is 27-54.

39. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises X_n(X^aX^b)_z motif,

wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), wherein n is 27-54, and wherein z is 1-4.

40. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵X_n(X^aX^b)_z motif,

wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q), wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), wherein n is 27-54, and wherein z is 1-4.

41. The humanized antibody or binding fragment thereof of claim 40, wherein the X¹X²X³X⁴X⁵ motif is TTVHQ (SEQ ID NO:

153) or TSVHQ (SEQ ID NO;

     154), and wherein the (X^aX^b)_z motif is YXYXYX.

42. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises:

a CX¹X²X³X⁴X⁵ motif, wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q),

a cysteine motif selected from the group consisting of;

CX₁₀CX₅CX₅CXCX₇C (SEQ ID NO;

     41), CX₁₀CX₆CX₅CXCX₁₅C (SEQ ID NO;

     42), CX₁₁CXCX₅C (SEQ ID NO;

     43), CX₁₁CX₅CX₅CXCX₇C (SEQ ID NO;

     44), CX₁₀CX₆CX₅CXCX₁₃C (SEQ ID NO;

     45), CX₁₀CX₅CXCX₄CX₈C (SEQ ID NO;

     46), CX₁₀CX₆CX₆CXCX₇C (SEQ ID NO;

     47), CX₁₀CX₄CX₇CXCX₈C (SEQ ID NO;

     48), CX₁₀CX₄CX₇CXCX₇C (SEQ ID NO;

     49), CX₁₃CX₈CX₈C (SEQ ID NO;

     50), CX₁₀CX₆CX₅CXCX₇C (SEQ ID NO;

     51), CX₁₀CX₅CX₅C (SEQ ID NO;

     52), CX₁₀CX₅CX₆CXCX₇C (SEQ ID NO;

     53), CX₁₀CX₆CX₅CX₇CX₉C (SEQ ID NO;

     54), CX₉CX₇CX₅CXCX₇C (SEQ ID NO;

     55), CX₁₀CX₆CX₅CXCX₉C (SEQ ID NO;

     56), CX₁₀CXCX₄CX₅CX₁₁C (SEQ ID NO;

     57), CX₇CX₃CX₆CX₅CXCX₅CX₁₀C (SEQ ID NO;

     58), CX₁₀CXCX₄CX₅CXCX₂CX₃C (SEQ ID NO;

     59), CX₁₆CX₅CXC (SEQ ID NO;

     60), CX₆CX₄CXCX₄CX₅C (SEQ ID NO;

     61), CX₁₁CX₄CX₅CX₆CX₃C (SEQ ID NO;

     62), CX₈CX₂CX₆CX₅C (SEQ ID NO;

     63), CX₁₀CX₅CX₅CXCX₁₀C (SEQ ID NO;

     64), CX₁₀CXCX₆CX₄CXC (SEQ ID NO;

     65), CX₁₀CX₅CX₅CXCX₂C (SEQ ID NO;

     66), CX₁₄CX₂CX₃CXCXC (SEQ ID NO;

     67), CX₁₅CX₅CXC (SEQ ID NO;

     68), CX₄CX₆CX₉CX₂CX₁₁C (SEQ ID NO;

     69), CX₆CX₄CX₅CX₅CX₁₂C (SEQ ID NO;

     70), CX₇CX₃CXCXCX₄CX₅CX₉C (SEQ ID NO;

     71), CX₁₀CX₆CX₅C (SEQ ID NO;

     72), CX₇CX₃CX₅CX₅CX₉C (SEQ ID NO;

     73), CX₇CX₅CXCX₂C (SEQ ID NO;

     74), CX₁₀CXCX₆C (SEQ ID NO;

     75), CX₁₀CX₃CX₃CX₅CX₇CXCX₆C (SEQ ID NO;

     76), CX₁₀CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     77), CX₁₂CX₄CX₅CXCXCX₉CX₃C (SEQ ID NO;

     78), CX₁₂CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     79), CX₁₀CX₆CX₅CXCX₁₁C (SEQ ID NO;

     80), CX₁₆CX₅CXCXCX₁₄C (SEQ ID NO;

     81), CX₁₀CX₅CXCX₈CX₆C (SEQ ID NO;

     82), CX₁₂CX₄CX₅CX₈CX₂C (SEQ ID NO;

     83), CX₁₂CX₅CX₅CXCX₈C (SEQ ID NO;

     84), CX₁₀CX₆CX₅CXCX₄CXCX₉C (SEQ ID NO;

     85), CX₁₁CX₄CX₅CX₈CX₂C (SEQ ID NO;

     86), CX₁₀CX₆CX₅CX₈CX₂C (SEQ ID NO;

     87), CX₁₀CX₆CX₅CXCX₈C (SEQ ID NO;

     88), CX₁₀CX₆CX₅CXCX₃CX₈CX₂C (SEQ ID NO;

     89), CX₁₀CX₆CX₅CX₃CX₈C (SEQ ID NO;

     90), CX₁₀CX₆CX₅CXCX₂CX₆CX₅C (SEQ ID NO;

     91), CX₇CX₆CX₃CX₃CX₉C (SEQ ID NO;

     92), CX₉CX₈CX₅CX₆CX₅C (SEQ ID NO;

     93), CX₁₀CX₂CX₂CX₇CXCX₁₁CX₅C (SEQ ID NO;

     94), and CX₁₀CX₆CX₅CXCX₂CX₈CX₄C (SEQ ID NO;

     95),

a (X^aX^b)_z motif, wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of;

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein z is 1-4.

43. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises:

a CX¹X²X³X⁴X⁵ motif, wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q);

a cysteine motif selected from the group consisting of;

wherein the cysteine motif is selected from the group consisting of;

CCX₃CXCX₃CX₂CCXCX₅CX₉CX₅CXC (SEQ ID NO;

     96), CX₆CX₂CX₅CX₄CCXCX₄CX₆CXC (SEQ ID NO;

     97), CX₇CXCX₅CX₄CCCX₄CX₆CXC (SEQ ID NO;

     98), CX₉CX₃CXCX₂CXCCCX₆CX₄C (SEQ ID NO;

     99), CX₅CX₃CXCX₄CX₄CCX₁₀CX₂CC (SEQ ID NO;

     100), CX₅CXCX₁CXCX₃CCX₃CX₄CX₁₀C (SEQ ID NO;

     101), CX₉CCCX₃CX₄CCCX₅CX₆C (SEQ ID NO;

     102), CCX₈CX₅CX₄CX₃CX₄CCXCX₁C (SEQ ID NO;

     103), CCX₆CCX₅CCCX₄CX₄CX₁₂C (SEQ ID NO;

     104), CX₆CX₂CX₃CCCX₄CX₅CX₃CX₃C (SEQ ID NO;

     105), CX₃CX₅CX₆CX₄CCXCX₅CX₄CXC (SEQ ID NO;

     106), CX₄CX₄CCX₄CX₄CXCX₁₁CX₂CXC (SEQ ID NO;

     107), CX₅CX₂CCX₅CX₄CCX₃CCX₇C (SEQ ID NO;

     108), CX₅CX₅CX₃CX₂CXCCX₄CX₇CXC (SEQ ID NO;

     109), CX₃CX₇CX₃CX₄CCXCX₂CX₅CX₂C (SEQ ID NO;

     110), CX₉CX₃CXCX₄CCX₅CCCX₆C (SEQ ID NO;

     111), CX₉CX₃CXCX₂CXCCX₆CX₃CX₃C (SEQ ID NO;

     112), CX₈CCXCX₃CCX₃CXCX₃CX₄C (SEQ ID NO;

     113), CX₉CCX₄CX₂CXCCXCX₄CX₃C (SEQ ID NO;

     114), CX₁₀CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     115), CX₉CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     116), CX₆CCXCX₅CX₄CCXCX₅CX₂C (SEQ ID NO;

     117), CX₆CCXCX₃CXCCX₃CX₄CC (SEQ ID NO;

     118), CX₆CCXCX₃CXCX₂CXCX₄CX₈C (SEQ ID NO;

     119), CX₄CX₂CCX₃CXCX₄CCX₂CX₃C (SEQ ID NO;

     120), CX₃CX₅CX₃CCCX₄CX₉C (SEQ ID NO;

     121), CCX₉CX₃CXCCX₃CX₅C (SEQ ID NO;

     122), CX₉CX₂CX₃CX₄CCX₄CX₅C (SEQ ID NO;

     123), CX₉CX₇CX₄CCXCX₇CX₃C (SEQ ID NO;

     124), CX₉CX₃CCCX₁₀CX₂CX₃C (SEQ ID NO;

     125), CX₃CX₅CX₅CX₄CCX₁₀CX₆C (SEQ ID NO;

     126), CX₉CX₅CX₄CCXCX₅CX₄C (SEQ ID NO;

     127), CX₇CXCX₆CX₄CCCX₁₀C (SEQ ID NO;

     128), CX₈CX₂CX₄CCX₄CX₃CX₃C (SEQ ID NO;

     129), CX₇CX₅CXCX₄CCX₇CX₄C (SEQ ID NO;

     130), CX₁₁CX₃CX₄CCCX₈CX₂C (SEQ ID NO;

     131), CX₂CX₃CX₄CCX₄CX₅CX₁₅C (SEQ ID NO;

     132), CX₉CX₅CX₄CCX₇C (SEQ ID NO;

     133), CX₉CX₇CX₃CX₂CX₆C (SEQ ID NO;

     134), CX₉CX₅CX₄CCX₁₄C (SEQ ID NO;

     135), CX₉CX₅CX₄CCX₈C (SEQ ID NO;

     136), CX₉CX₆CX₄CCXC (SEQ ID NO;

     137), CX₅CCX₇CX₄CX₁₂ (SEQ ID NO;

     138), CX₁₀CX₃CX₄CCX₄C (SEQ ID NO;

     139), CX₉CX₄CCX₅CX₄C (SEQ ID NO;

     140), CX₁₀CX₃CX₄CX₇CXC (SEQ ID NO;

     141), CX₇CX₇CX₂CX₂CX₃C (SEQ ID NO;

     142), CX₉CX₄CX₄CCX₆C (SEQ ID NO;

     143), CX₇CXCX₃CXCX₆C (SEQ ID NO;

     144), CX₇CXCX₄CXCX₄C (SEQ ID NO;

     145), CX₉CX₅CX₄C (SEQ ID NO;

     146), CX₃CX₆CX₈C (SEQ ID NO;

     147), CX₁₀CXCX₄C (SEQ ID NO;

     148), CX₁₀CCX₄C (SEQ ID NO;

     149), CX₁₅C (SEQ ID NO;

     150), CX₁₀C (SEQ ID NO;

     151), and CX₉C (SEQ ID NO;

     152); and

a (X^aX^b)_z motif, wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of;

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein z is 1-4.

44. The humanized antibody or binding fragment thereof of claim 20, wherein the ultralong CDR3 comprises an additional sequence that is a linker.

45. The humanized antibody or binding fragment thereof of claim 44, wherein the linker is linked to a C-terminus, a N-terminus, or both C-terminus and N-terminus of the non-antibody sequence.

46. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 is a ruminant CDR3.

47. The humanized antibody or binding fragment thereof of claim 46, wherein the ruminant is a cow.

48. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

735.

49. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

737.

50. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

739.

51. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

741.

52. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

743.

53. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

745.

54. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

747.

55. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

749.

56. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises an amino acid sequence of:

(i) any one of GSKHRLRDYFLYNE (SEQ ID NO;

     501), GSKHRLRDYFLYN (SEQ ID NO;

     502), GSKHRLRDYFLY (SEQ ID NO;

     503), GSKHRLRDYFL (SEQ ID NO;

     504), GSKHRLRDYF (SEQ ID NO;

     505), GSKHRLRDY (SEQ ID NO;

     506), or GSKHRLRD (SEQ ID NO;

     507);

(ii) any one of EAGGPDYRNGYNY (SEQ ID NO;

     508), EAGGPDYRNGYN (SEQ ID NO;

     509), EAGGPDYRNGY (SEQ ID NO;

     510), EAGGPDYRNG (SEQ ID NO;

     511), EAGGPDYRN (SEQ ID NO;

     512), EAGGPDYR (SEQ ID NO;

     513), EAGGPDY (SEQ ID NO;

     514), or EAGGPD (SEQ ID NO;

     515);

(iii) any one of EAGGPIWHDDVKY (SEQ ID NO;

     516), EAGGPIWHDDVK (SEQ ID NO;

     517), EAGGPIWHDDV (SEQ ID NO;

     518), EAGGPIWHDD (SEQ ID NO;

     519), EAGGPIWHD (SEQ ID NO;

     520), EAGGPIWH (SEQ ID NO;

     521), EAGGPIW (SEQ ID NO;

     522), or EAGGPI (SEQ ID NO;

     523);

(iv) any one of GTDYTIDDQGI (SEQ ID NO;

     524), GTDYTIDDQG (SEQ ID NO;

     525), GTDYTIDDQ (SEQ ID NO;

     526), GTDYTIDD (SEQ ID NO;

     527), GTDYTID (SEQ ID NO;

     528), or GTDYTI (SEQ ID NO;

     529);

(v) any one of DKGDSDYDYNL (SEQ ID NO;

     530), DKGDSDYDYN (SEQ ID NO;

     531), DKGDSDYDY (SEQ ID NO;

     532), DKGDSDYD (SEQ ID NO;

     533), DKGDSDY (SEQ ID NO;

     534), DKGDSD (SEQ ID NO;

     535);

(vi) TSVHQETKKYQS (SEQ ID NO;

     498).

57. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises an amino acid sequence of:

(i) any one of YGPNYEEWGDYLATLDV (SEQ ID NO;

     536), GPNYEEWGDYLATLDV (SEQ ID NO;

     537), PNYEEWGDYLATLDV (SEQ ID NO;

     538), NYEEWGDYLATLDV (SEQ ID NO;

     539), YEEWGDYLATLDV (SEQ ID NO;

     540), or EEWGDYLATLDV (SEQ ID NO;

     541);

(ii) any one of YDFYDGYYNYHYMDV (SEQ ID NO;

     542), DFYDGYYNYHYMDV (SEQ ID NO;

     543), FYDGYYNYHYMDV (SEQ ID NO;

     544), YDGYYNYHYMDV (SEQ ID NO;

     545), DGYYNYHYMDV (SEQ ID NO;

     546), GYYNYHYMDV (SEQ ID NO;

     547), or YYNYHYMDV (SEQ ID NO;

     548);

(iii) any one of YDFNDGYYNYHYMDV (SEQ ID NO;

     549), DFYDGYYNYHYMDV (SEQ ID NO;

     550), FYDGYYNYHYMDV (SEQ ID NO;

     551), YDGYYNYHYMDV (SEQ ID NO;

     552), DGYYNYHYMDV (SEQ ID NO;

     553), or GYYNYHYMDV (SEQ ID NO;

     554);

(iv) any one of QGIRYQGSGTFWYFDV (SEQ ID NO;

     555), GIRYQGSGTFWYFDV (SEQ ID NO;

     556), IRYQGSGTFWYFDV (SEQ ID NO;

     557), RYQGSGTFWYFDV (SEQ ID NO;

     558), YQGSGTFWYFDV (SEQ ID NO;

     559), QGSGTFWYFDV (SEQ ID NO;

     560), GSGTFWYFDV (SEQ ID NO;

     561), SGTFWYFDV (SEQ ID NO;

     562), or GTFWYFDV (SEQ ID NO;

     563);

(v) any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569);

or

(vi) SYTYNYEWHVDV (SEQ ID NO;

     499).

58. The humanized antibody or binding fragment thereof of claim 1, wherein the ultralong CDR3 comprises an amino acid sequence of:

(i) any one of GSKHRLRDYFLYNE (SEQ ID NO;

     501), GSKHRLRDYFLYN (SEQ ID NO;

     502), GSKHRLRDYFLY (SEQ ID NO;

     503), GSKHRLRDYFL (SEQ ID NO;

     504), GSKHRLRDYF (SEQ ID NO;

     505), GSKHRLRDY (SEQ ID NO;

     506), or GSKHRLRD (SEQ ID NO;

     507), and any one of YGPNYEEWGDYLATLDV (SEQ ID NO;

     536), GPNYEEWGDYLATLDV (SEQ ID NO;

     537), PNYEEWGDYLATLDV (SEQ ID NO;

     538), NYEEWGDYLATLDV (SEQ ID NO;

     539), YEEWGDYLATLDV (SEQ ID NO;

     540), or EEWGDYLATLDV (SEQ ID NO;

     541);

(ii) any one of EAGGPDYRNGYNY (SEQ ID NO;

     508), EAGGPDYRNGYN (SEQ ID NO;

     509), EAGGPDYRNGY (SEQ ID NO;

     510), EAGGPDYRNG (SEQ ID NO;

     511), EAGGPDYRN (SEQ ID NO;

     512), EAGGPDYR (SEQ ID NO;

     513), EAGGPDY (SEQ ID NO;

     514), or EAGGPD (SEQ ID NO;

     515), and any one of YDFYDGYYNYHYMDV (SEQ ID NO;

     542), DFYDGYYNYHYMDV (SEQ ID NO;

     543), FYDGYYNYHYMDV (SEQ ID NO;

     544), YDGYYNYHYMDV (SEQ ID NO;

     545), DGYYNYHYMDV (SEQ ID NO;

     546), GYYNYHYMDV (SEQ ID NO;

     547), or YYNYHYMDV (SEQ ID NO;

     548);

(iii) any one of EAGGPIWHDDVKY (SEQ ID NO;

     516), EAGGPIWHDDVK (SEQ ID NO;

     517), EAGGPIWHDDV (SEQ ID NO;

     518), EAGGPIWHDD (SEQ ID NO;

     519), EAGGPIWHD (SEQ ID NO;

     520), EAGGPIWH (SEQ ID NO;

     521), EAGGPIW (SEQ ID NO;

     522), or EAGGPI (SEQ ID NO;

     523), and any one of YDFNDGYYNYHYMDV (SEQ ID NO;

     549), DFYDGYYNYHYMDV (SEQ ID NO;

     550), FYDGYYNYHYMDV (SEQ ID NO;

     551), YDGYYNYHYMDV (SEQ ID NO;

     552), DGYYNYHYMDV (SEQ ID NO;

     553), or GYYNYHYMDV (SEQ ID NO;

     554);

(iv) any one of GTDYTIDDQGI (SEQ ID NO;

     524), GTDYTIDDQG (SEQ ID NO;

     525), GTDYTIDDQ (SEQ ID NO;

     526), GTDYTIDD (SEQ ID NO;

     527), GTDYTID (SEQ ID NO;

     528), or GTDYTI (SEQ ID NO;

     529), and any one of QGIRYQGSGTFWYFDV (SEQ ID NO;

     555), GIRYQGSGTFWYFDV (SEQ ID NO;

     556), IRYQGSGTFWYFDV (SEQ ID NO;

     557), RYQGSGTFWYFDV (SEQ ID NO;

     558), YQGSGTFWYFDV (SEQ ID NO;

     559), QGSGTFWYFDV (SEQ ID NO;

     560), GSGTFWYFDV (SEQ ID NO;

     561), SGTFWYFDV (SEQ ID NO;

     562), or GTFWYFDV (SEQ ID NO;

     563);

(v) any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569), and any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569);

or

(vi) TSVHQETKKYQS (SEQ ID NO;

     498) and SYTYNYEWHVDV (SEQ ID NO;

     499).

59. The humanized antibody or binding fragment thereof of claim 1, wherein the humanized antibody or binding fragment thereof comprises a light chain variable region comprising a sequence selected from the group of:

(i) SEQ ID NO;

750, (ii) SEQ ID NO;

751, (iii) SEQ ID NO;

752, and (iv) SEQ ID NO;

753.

60. The humanized antibody or binding fragment thereof of claim 59, wherein the light chain variable region comprises a lambda light chain variable region sequence.

61. The humanized antibody or binding fragment thereof of claim 59, wherein the light chain variable region comprises a human lambda light chain variable region sequence.

62. The humanized antibody or binding fragment thereof of claim 59, wherein the light chain variable region comprises a VL1-51 germline sequence.

63. The humanized antibody or binding fragment thereof of claim 59, wherein the light chain variable region is derived from a VL1-51 germline sequence.

64. The humanized antibody or binding fragment thereof of claim 63, wherein the VL1-51 germline sequence comprises a CDR1 comprising Ile29Val and Asn32Gly substitution based on Kabat numbering.

65. The humanized antibody or binding fragment thereof of claim 63, wherein the VL1-51 germline sequence comprises a CDR2 comprising a substitution of DNN to GDT.

66. The humanized antibody or binding fragment thereof of claim 63, wherein the VL1-51 germline sequence comprises a CDR2 comprising a substitution of DNNKRP (SEQ ID NO:

471) to GDTSRA (SEQ ID NO;

     472).

67. The humanized antibody or binding fragment thereof of claim 63, wherein the VL1-51 germline sequence comprises a S2A, T5N, P8S, A12G, A13S, and P14L substitution based on Kabat numbering.

68. The humanized antibody or binding fragment thereof of claim 63, wherein the VL1-51 germline sequence comprises a S2A, T5N, P8S, A12G, A13S, and P14L substitution based on Kabat numbering, and a CDR2 comprising a substitution of DNN to GDT.

69. The humanized antibody or binding fragment thereof of claim 1, wherein the humanized antibody or binding fragment thereof comprising:

(a) a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NO;

740, SEQ ID NO;

741, SEQ ID NO;

742, and SEQ ID NO;

743; and

(b) a light chain variable region comprising SEQ ID NO;

750.

70. A polynucleotide encoding the heavy chain variable region of the humanized antibody or binding fragment thereof of any one of claims 1-69.

71. A polynucleotide encoding the light chain variable region of the humanized antibody or binding fragment thereof of any one of claims 59-69.

73. A vector comprising the polynucleotide of any one of claims 70-72.

74. A host cell comprising the vector of claim 73.

117. The library of claim 76, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

735.113.) The library of claim 71, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO;

737.

214. The humanized antibody or binding fragment thereof of claim 59, wherein the light chain variable region comprises an amino acid sequence of SEQ ID NO:

750, an amino acid sequence of SEQ ID NO;

754, and an amino acid sequence of SEQ ID NO;

755.

215. The humanized antibody or binding fragment thereof of claim 214, further comprising an amino acid sequence of SEQ ID NO:

756.

216. The humanized antibody or binding fragment thereof of claim 59, wherein the light chain variable region comprises an amino acid sequence of SEQ ID NO:

751, an amino acid sequence of SEQ ID NO;

754, and an amino acid sequence of SEQ ID NO;

755.

217. The humanized antibody or binding fragment thereof of claim 216, further comprising an amino acid sequence of SEQ ID NO:

756.

218. The humanized antibody or binding fragment thereof of claim 59, wherein the light chain variable region comprises an amino acid sequence of SEQ ID NO:

752, an amino acid sequence of SEQ ID NO;

754, and an amino acid sequence of SEQ ID NO;

755.

219. The humanized antibody or binding fragment thereof of claim 218, further comprising an amino acid sequence of SEQ ID NO:

756.

220. The humanized antibody or binding fragment thereof of claim 59, wherein the light chain variable region comprises an amino acid sequence of SEQ ID NO:

753, an amino acid sequence of SEQ ID NO;

754, and an amino acid sequence of SEQ ID NO;

755.

221. The humanized antibody or binding fragment thereof of claim 220, further comprising an amino acid sequence of SEQ ID NO:

756.

222. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

737 and SEQ ID NO;

500, wherein the ultralong CDR3 comprises an amino acid sequence of SEQ ID NO;

498 and SEQ ID NO;

499.

223. The humanized antibody or binding fragment thereof of claim 222, further comprising a light chain variable region comprising an amino acid sequence of SEQ ID NO:

750, an amino acid sequence of SEQ ID NO;

754, and an amino acid sequence of SEQ ID NO;

755.

224. The humanized antibody or binding fragment thereof of claim 1, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

739 and SEQ ID NO;

500, wherein the ultralong CDR3 comprises an amino acid sequence of SEQ ID NO;

498 and SEQ ID NO;

499.

225. The humanized antibody or binding fragment thereof of claim 224, further comprising a light chain variable region comprising an amino acid sequence of SEQ ID NO:

750, an amino acid sequence of SEQ ID NO;

754, and an amino acid sequence of SEQ ID NO;

755.

72. A polynucleotide encoding a heavy chain variable region that comprises an ultralong CDR3, wherein the polynucleotide comprises a sequence selected from the group consisting of SEQ ID NO:

490, SEQ ID NO;

491, SEQ ID NO;

492, SEQ ID NO;

493, SEQ ID NO;

494, SEQ ID NO;

495, SEQ ID NO;

496, and SEQ ID NO;

497.

75. A nucleic acid library comprising a plurality of polynucleotides comprising sequences coding for humanized antibodies or binding fragments thereof, wherein the antibodies or binding fragments thereof comprise a heavy chain variable region comprising:

(a) an amino acid sequence selected from the group consisting of;

(i) SEQ ID NO;

734 or SEQ ID NO;

735,

(ii) SEQ ID NO;

736 or SEQ ID NO;

737,

(iii) SEQ ID NO;

738 or SEQ ID NO;

739,

(iv) SEQ ID NO;

740 or SEQ ID NO;

741,

(v) SEQ ID NO;

742 or SEQ ID NO;

743,

(vi) SEQ ID NO;

744 or SEQ ID NO;

745,

(vii) SEQ ID NO;

746 or SEQ ID NO 747, and

(viii) SEQ ID NO;

748 or SEQ ID NO;

749; and

(b) an ultralong CDR3.

77. The library of claim 75 or 76, wherein the ultralong CDR3 is 35 amino acids in length or longer, 40 amino acids in length or longer, 45 amino acids in length or longer, 50 amino acids in length or longer, 55 amino acids in length or longer, or 60 amino acids in length or longer.

78. The library of claim 77, wherein the ultralong CDR3 is 35 amino acids in length or longer.

79. The library of claim 75 or 76, wherein the ultralong CDR3 comprises 3 or more cysteine residues, 4 or more cysteine residues, 5 or more cysteine residues, 6 or more cysteine residues, 7 or more cysteine residues, 8 or more cysteine residues, 9 or more cysteine residues, 10 or more cysteine residues, 11 or more cysteine residues, or 12 or more cysteine residues.

80. The library of claim 79, wherein the ultralong CDR3 comprises 3 or more cysteine residues.

76. A library of humanized antibodies or binding fragments thereof, wherein the antibodies or binding fragments thereof comprise a heavy chain variable region comprising:

(a) an amino acid sequence selected from the group consisting of;

(i) SEQ ID NO;

734 or SEQ ID NO;

735,

(ii) SEQ ID NO;

736 or SEQ ID NO;

737,

(iii) SEQ ID NO;

738 or SEQ ID NO;

739,

(iv) SEQ ID NO;

740 or SEQ ID NO;

741,

(v) SEQ ID NO;

742 or SEQ ID NO;

743,

(vi) SEQ ID NO;

744 or SEQ ID NO;

745,

(vii) SEQ ID NO;

746 or SEQ ID NO 747, and

(viii) SEQ ID NO;

748 or SEQ ID NO;

749; and

(b) an ultralong CDR3.

81. The library of claim 76, wherein the antibodies or binding fragments thereof comprise a cysteine motif.

82. The library of claim 76, wherein the cysteine motif is selected from the group consisting of:

CX₁₀CX₅CX₅CXCX₇C (SEQ ID NO;

     41), CX₁₀CX₆CX₅CXCX₁₅C (SEQ ID NO;

     42), CX₁₁CXCX₅C (SEQ ID NO;

     43), CX₁₁CX₅CX₅CXCX₇C (SEQ ID NO;

     44), CX₁₀CX₆CX₅CXCX₁₃C (SEQ ID NO;

     45), CX₁₀CX₅CXCX₄CX₈C (SEQ ID NO;

     46), CX₁₀CX₆CX₆CXCX₇C (SEQ ID NO;

     47), CX₁₀CX₄CX₇CXCX₈C (SEQ ID NO;

     48), CX₁₀CX₄CX₇CXCX₇C (SEQ ID NO;

     49), CX₁₃CX₈CX₈C (SEQ ID NO;

     50), CX₁₀CX₆CX₅CXCX₇C (SEQ ID NO;

     51), CX₁₀CX₅CX₅C (SEQ ID NO;

     52), CX₁₀CX₅CX₆CXCX₇C (SEQ ID NO;

     53), CX₁₀CX₆CX₅CX₇CX₉C (SEQ ID NO;

     54), CX₉CX₇CX₅CXCX₇C (SEQ ID NO;

     55), CX₁₀CX₆CX₅CXCX₉C (SEQ ID NO;

     56), CX₁₀CXCX₄CX₅CX₁₁C (SEQ ID NO;

     57), CX₇CX₃CX₆CX₅CXCX₅CX₁₀C (SEQ ID NO;

     58), CX₁₀CXCX₄CX₅CXCX₂CX₃C (SEQ ID NO;

     59), CX₁₆CX₅CXC (SEQ ID NO;

     60), CX₆CX₄CXCX₄CX₅C (SEQ ID NO;

     61), CX₁₁CX₄CX₅CX₆CX₃C (SEQ ID NO;

     62), CX₈CX₂CX₆CX₅C (SEQ ID NO;

     63), CX₁₀CX₅CX₅CXCX₁₀C (SEQ ID NO;

     64), CX₁₀CXCX₆CX₄CXC (SEQ ID NO;

     65), CX₁₀CX₅CX₅CXCX₂C (SEQ ID NO;

     66), CX₁₄CX₂CX₃CXCXC (SEQ ID NO;

     67), CX₁₅CX₅CXC (SEQ ID NO;

     68), CX₄CX₆CX₉CX₂CX₁₁C (SEQ ID NO;

     69), CX₆CX₄CX₅CX₅CX₁₂C (SEQ ID NO;

     70), CX₇CX₃CXCXCX₄CX₅CX₉C (SEQ ID NO;

     71), CX₁₀CX₆CX₅C (SEQ ID NO;

     72), CX₇CX₃CX₅CX₅CX₉C (SEQ ID NO;

     73), CX₇CX₅CXCX₂C (SEQ ID NO;

     74), CX₁₀CXCX₆C (SEQ ID NO;

     75), CX₁₀CX₃CX₃CX₅CX₇CXCX₆C (SEQ ID NO;

     76), CX₁₀CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     77), CX₁₂CX₄CX₅CXCXCX₉CX₃C (SEQ ID NO;

     78), CX₁₂CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     79), CX₁₀CX₆CX₅CXCX₁₁C (SEQ ID NO;

     80), CX₁₆CX₅CXCXCX₁₄C (SEQ ID NO;

     81), CX₁₀CX₅CXCX₈CX₆C (SEQ ID NO;

     82), CX₁₂CX₄CX₅CX₈CX₂C (SEQ ID NO;

     83), CX₁₂CX₅CX₅CXCX₈C (SEQ ID NO;

     84), CX₁₀CX₆CX₅CXCX₄CXCX₉C (SEQ ID NO;

     85), CX₁₁CX₄CX₅CX₈CX₂C (SEQ ID NO;

     86), CX₁₀CX₆CX₅CX₈CX₂C (SEQ ID NO;

     87), CX₁₀CX₆CX₅CXCX₈C (SEQ ID NO;

     88), CX₁₀CX₆CX₅CXCX₃CX₈CX₂C (SEQ ID NO;

     89), CX₁₀CX₆CX₅CX₃CX₈C (SEQ ID NO;

     90), CX₁₀CX₆CX₅CXCX₂CX₆CX₅C (SEQ ID NO;

     91), CX₇CX₆CX₃CX₃CX₉C (SEQ ID NO;

     92), CX₉CX₈CX₅CX₆CX₅C (SEQ ID NO;

     93), CX₁₀CX₂CX₂CX₇CXCX₁₁CX₅C (SEQ ID NO;

     94), and CX₁₀CX₆CX₅CXCX₂CX₈CX₄C (SEQ ID NO;

     95).

83. The library of claim 81, wherein the cysteine motif is selected from the group consisting of:

CCX₃CXCX₃CX₂CCXCX₅CX₉CX₅CXC (SEQ ID NO;

     96), CX₆CX₂CX₅CX₄CCXCX₄CX₆CXC (SEQ ID NO;

     97), CX₇CXCX₅CX₄CCCX₄CX₆CXC (SEQ ID NO;

     98), CX₉CX₃CXCX₂CXCCCX₆CX₄C (SEQ ID NO;

     99), CX₅CX₃CXCX₄CX₄CCX₁₀CX₂CC (SEQ ID NO;

     100), CX₅CXCX₁CXCX₃CCX₃CX₄CX₁₀C (SEQ ID NO;

     101), CX₉CCCX₃CX₄CCCX₅CX₆C (SEQ ID NO;

     102), CCX₈CX₅CX₄CX₃CX₄CCXCX₁C (SEQ ID NO;

     103), CCX₆CCX₅CCCX₄CX₄CX₁₂C (SEQ ID NO;

     104), CX₆CX₂CX₃CCCX₄CX₅CX₃CX₃C (SEQ ID NO;

     105), CX₃CX₅CX₆CX₄CCXCX₅CX₄CXC (SEQ ID NO;

     106), CX₄CX₄CCX₄CX₄CXCX₁₁CX₂CXC (SEQ ID NO;

     107), CX₅CX₂CCX₅CX₄CCX₃CCX₇C (SEQ ID NO;

     108), CX₅CX₅CX₃CX₂CXCCX₄CX₇CXC (SEQ ID NO;

     109), CX₃CX₇CX₃CX₄CCXCX₂CX₅CX₂C (SEQ ID NO;

     110), CX₉CX₃CXCX₄CCX₅CCCX₆C (SEQ ID NO;

     111), CX₉CX₃CXCX₂CXCCX₆CX₃CX₃C (SEQ ID NO;

     112), CX₈CCXCX₃CCX₃CXCX₃CX₄C (SEQ ID NO;

     113), CX₉CCX₄CX₂CXCCXCX₄CX₃C (SEQ ID NO;

     114), CX₁₀CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     115), CX₉CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     116), CX₆CCXCX₅CX₄CCXCX₅CX₂C (SEQ ID NO;

     117), CX₆CCXCX₃CXCCX₃CX₄CC (SEQ ID NO;

     118), CX₆CCXCX₃CXCX₂CXCX₄CX₈C (SEQ ID NO;

     119), CX₄CX₂CCX₃CXCX₄CCX₂CX₃C (SEQ ID NO;

     120), CX₃CX₅CX₃CCCX₄CX₉C (SEQ ID NO;

     121), CCX₉CX₃CXCCX₃CX₅C (SEQ ID NO;

     122), CX₉CX₂CX₃CX₄CCX₄CX₅C (SEQ ID NO;

     123), CX₉CX₇CX₄CCXCX₇CX₃C (SEQ ID NO;

     124), CX₉CX₃CCCX₁₀CX₂CX₃C (SEQ ID NO;

     125), CX₃CX₅CX₅CX₄CCX₁₀CX₆C (SEQ ID NO;

     126), CX₉CX₅CX₄CCXCX₅CX₄C (SEQ ID NO;

     127), CX₇CXCX₆CX₄CCCX₁₀C (SEQ ID NO;

     128), CX₈CX₂CX₄CCX₄CX₃CX₃C (SEQ ID NO;

     129), CX₇CX₅CXCX₄CCX₇CX₄C (SEQ ID NO;

     130), CX₁₁CX₃CX₄CCCX₈CX₂C (SEQ ID NO;

     131), CX₂CX₃CX₄CCX₄CX₅CX₁₅C (SEQ ID NO;

     132), CX₉CX₅CX₄CCX₇C (SEQ ID NO;

     133), CX₉CX₇CX₃CX₂CX₆C (SEQ ID NO;

     134), CX₉CX₅CX₄CCX₁₄C (SEQ ID NO;

     135), CX₉CX₅CX₄CCX₈C (SEQ ID NO;

     136), CX₉CX₆CX₄CCXC (SEQ ID NO;

     137), CX₅CCX₇CX₄CX₁₂ (SEQ ID NO;

     138), CX₁₀CX₃CX₄CCX₄C (SEQ ID NO;

     139), CX₉CX₄CCX₅CX₄C (SEQ ID NO;

     140), CX₁₀CX₃CX₄CX₇CXC (SEQ ID NO;

     141), CX₇CX₇CX₂CX₂CX₃C (SEQ ID NO;

     142), CX₉CX₄CX₄CCX₆C (SEQ ID NO;

     143), CX₇CXCX₃CXCX₆C (SEQ ID NO;

     144), CX₇CXCX₄CXCX₄C (SEQ ID NO;

     145), CX₉CX₅CX₄C (SEQ ID NO;

     146), CX₃CX₆CX₈C (SEQ ID NO;

     147), CX₁₀CXCX₄C (SEQ ID NO;

     148), CX₁₀CCX₄C (SEQ ID NO;

     149), CX₁₅C (SEQ ID NO;

     150), CX₁₀C (SEQ ID NO;

     151), and CX₉C (SEQ ID NO;

     152).

84. The library of claim 76, wherein the ultralong CDR3 comprises 2 to 6 disulfide bonds.

85. The library of claim 76, wherein the ultralong CDR3 comprises SEQ ID NO:

40 or a derivative thereof.

86. The library of claim 76, wherein the ultralong CDR3 comprises amino acid residues 3-6 of any of one SEQ ID NO:

1-4.

87. The library of claim 76, wherein the ultralong CDR3 comprises a non-human DH or a derivative thereof.

88. The library of claim 87, wherein the non-human DH is SEQ ID NO:

5, SEQ ID NO;

6, SEQ ID NO;

7, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, or SEQ ID NO;

12

89. The library of claim 76, wherein the ultralong CDR3 comprises a JH sequence or a derivative thereof.

90. The library of claim 89, wherein the JH sequence comprises amino acids as positions 5-15 of SEQ ID NO:

13, SEQ ID NO;

14, SEQ ID NO;

15, SEQ ID NO;

16, or SEQ ID NO;

17.

91. The library of claim 76, wherein the ultralong CDR3 comprises:

a sequence derived from a non-human VH sequence or a derivative thereof;

a sequence derived from a non-human DH sequence or a derivative thereof; and

/or

a sequence derived from a JH sequence or derivative thereof.

92. The library of claim 91, wherein the ultralong CDR3 comprises an additional amino acid sequence comprising two to six amino acid residues or more positioned between the VH sequence and the DH sequence.

93. The library of claim 92, wherein the additional amino acid sequence is selected from the group consisting of:

IR, IF, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

20 or SEQ ID NO;

21.

94. The library of claim 76, wherein the ultralong CDR3 comprises a sequence derived from or based on SEQ ID NO:

22, SEQ ID NO;

23, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

26, SEQ ID NO;

27, or SEQ ID NO;

28.

95. The library of claim 76, wherein the ultralong CDR3 comprises a non-bovine sequence or a non-antibody sequence.

96. The library of claim 95, wherein the non-antibody sequence is a synthetic sequence.

97. The library of claim 95, wherein the non-antibody sequence is a cytokine sequence, a lymphokine sequence, a chemokine sequence, a growth factor sequence, a hormone sequence, or a toxin sequence.

98. The library of claim 95, wherein the non-antibody sequence is an IL-8 sequence, an IL-21 sequence, an SDF-1 (alpha) sequence, a somatostatin sequence, a chlorotoxin sequence, a Pro-TxII sequence, a ziconotide sequence, an ADWX-1 sequence, an HsTx1 sequence, an OSK1 sequence, a Pi2 sequence, a Hongotoxin (HgTX) sequence, a Margatoxin sequence, an Agitoxin-2 sequence, a Pi3 sequence, a Kaliotoxin sequence, an Anuroctoxin sequence, a Charybdotoxin sequence, a Tityustoxin -K- alpha sequence, a Maurotoxin sequence, a Ceratotoxin 1 (CcoTx1) sequence, a CcoTx2 sequence, a CcoTx3 sequence, a Phrixotoxin 3 (PaurTx3) sequence, a Hanatoxin 1 sequence, a Phrixotoxin 1 sequence, a Huwentoxin-IV sequence, an α

-conotoxin ImI sequence, an α

-conotoxin EpI sequence, an α

-conotoxin PnIA sequence, an α

-conotoxin PnIB sequence, an α

-conotoxin MII sequence, an α

-conotoxin AuIA sequence, an α

-conotoxin AuIB sequence, an α

-conotoxin AuIC sequence, a conotoxin κ

-PVIIA sequence, a charybdotoxin sequence, a neurotoxin B-IV sequence, a crotamine sequence, a ω

-GVIA (conotoxin) sequence, a κ

-hefutoxin 1 sequence, a Css4 sequence, a Bj-xtrIT sequence, a BcIV sequence, a Hm-1 sequence, a Hm-2 sequence, a GsAF-I (β

-theraphotoxin-Gr1b) sequence, a Protoxin I (ProTx-I sequence, a β

-theraphotoxin-Tp1a) sequence, a Protoxin II (ProTx II) sequence, a Huwentoxin I sequence, a μ

-Conotoxin PIIIA sequence, a Jingzhaotoxin-III (β

-TRTX-Cj1a) sequence, a GsAF-II (Kappa-theraphotoxin-Gr2c) sequence, a ShK (Stichodactyla toxin) sequence, a HsTx1 sequence, a Guangxitoxin 1E (GxTx-1E) sequence, a Maurotoxin sequence, a Charybdotoxin (ChTX) sequence, an Iberiotoxin (IbTx) sequence, a Leiurotoxin 1 (scyllatoxin) sequence, a Tamapin sequence, a Kaliotoxin-1 (KTX) sequence, a Purotoxin1 (PT-1) sequence, or a GpTx-1 sequence, a MOKA Toxin sequence, a OSK1 (P12, K16, D20) sequence, a OSK1 (K16, D20) sequence, a HmK sequence, a ShK (K16, Y26, K29) sequence, a ShK (K16) sequence, a ShK-A (K16) sequence, a ShK (K16, E30) sequence, a ShK (Q21) sequence, a ShK (L21) sequence, a ShK (F21) sequence, a ShK (121) sequence, or a ShK (A21) sequence.

99. The library of claim 95, wherein the non-antibody sequence is any one of SEQ ID NOS:

475-481, 599-655, 666-698, 727-733, 808-810 and 831-835.

100. The library of claim 76, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵ motif, wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q).

101. The library of claim 100, wherein the X¹X²X³X⁴X⁵ motif is TTVHQ (SEQ ID NO:

153), TSVHQ (SEQ ID NO;

     154), SSVTQ (SEQ ID NO;

     155), STVHQ (SEQ ID NO;

     156), ATVRQ (SEQ ID NO;

     157), TTVYQ (SEQ ID NO;

     158), SPVHQ (SEQ ID NO;

     159), ATVYQ (SEQ ID NO;

     160), TAVYQ (SEQ ID NO;

     161), TNVHQ (SEQ ID NO;

     162), ATVHQ (SEQ ID NO;

     163), STVYQ (SEQ ID NO;

     164), TIVHQ (SEQ ID NO;

     165), AIVYQ (SEQ ID NO;

     166), TTVFQ (SEQ ID NO;

     167), AAVFQ (SEQ ID NO;

     168), GTVHQ (SEQ ID NO;

     169), ASVHQ (SEQ ID NO;

     170), TAVFQ (SEQ ID NO;

     171), ATVFQ (SEQ ID NO;

     172), AAAHQ (SEQ ID NO;

     173), VWYQ (SEQ ID NO;

     174), GTVFQ (SEQ ID NO;

     175), TAVHQ (SEQ ID NO;

     176), ITVHQ (SEQ ID NO;

     177), ITAHQ (SEQ ID NO;

     178), VTVHQ (SEQ ID NO;

     179);

AAVHQ (SEQ ID NO;

     180), GTVYQ (SEQ ID NO;

     181), TTVLQ (SEQ ID NO;

     182), TTTHQ (SEQ ID NO;

     183), or TTDYQ (SEQ ID NO;

     184).

102. The library of claim 76, wherein the ultralong CDR3 comprises a CX¹X²X³X⁴X⁵ motif.

103. The library of claim 102, wherein the CX¹X²X³X⁴X⁵ motif is CTTVHQ (SEQ ID NO:

185), CTSVHQ (SEQ ID NO;

     186), CSSVTQ (SEQ ID NO;

     187), CSTVHQ (SEQ ID NO;

     188), CATVRQ (SEQ ID NO;

     189), CTTVYQ (SEQ ID NO;

     190), CSPVHQ (SEQ ID NO;

     191), CATVYQ (SEQ ID NO;

     192), CTAVYQ (SEQ ID NO;

     193), CTNVHQ (SEQ ID NO;

     194), CATVHQ (SEQ ID NO;

     195), CSTVYQ (SEQ ID NO;

     196), CTIVHQ (SEQ ID NO;

     197), CAIVYQ (SEQ ID NO;

     198), CTTVFQ (SEQ ID NO;

     199), CAAVFQ (SEQ ID NO;

     200), CGTVHQ (SEQ ID NO;

     201), CASVHQ (SEQ ID NO;

     202), CTAVFQ (SEQ ID NO;

     203), CATVFQ (SEQ ID NO;

     204), CAAAHQ (SEQ ID NO;

     205), CVVVYQ (SEQ ID NO;

     206), CGTVFQ (SEQ ID NO;

     207), CTAVHQ (SEQ ID NO;

     208), CITVHQ (SEQ ID NO;

     209), CITAHQ (SEQ ID NO;

     210), CVTVHQ (SEQ ID NO;

     211);

CAAVHQ (SEQ ID NO;

     212), CGTVYQ (SEQ ID NO;

     213), CTTVLQ (SEQ ID NO;

     214), CTTTHQ (SEQ ID NO;

     215), or CTTDYQ (SEQ ID NO;

     216).

104. The library of claim 76, wherein the ultralong CDR3 comprises a (X^aX^b)_z motif, wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein z is 1-4.

105. The library of claim 104, wherein the (X^aX^b)_z motif is CYTYNYEF (SEQ ID NO:

217), HYTYTYDF (SEQ ID NO;

     218), HYTYTYEW (SEQ ID NO;

     219), KHRYTYEW (SEQ ID NO;

     220), NYIYKYSF (SEQ ID NO;

     221), PYIYTYQF (SEQ ID NO;

     222), SFTYTYEW (SEQ ID NO;

     223), SYIYIYQW (SEQ ID NO;

     224), SYNYTYSW (SEQ ID NO;

     225), SYSYSYEY (SEQ ID NO;

     226), SYTYNYDF (SEQ ID NO;

     227), SYTYNYEW (SEQ ID NO;

     228), SYTYNYQF (SEQ ID NO;

     229), SYVWTHNF (SEQ ID NO;

     230), TYKYVYEW (SEQ ID NO;

     231), TYTYTYEF (SEQ ID NO;

     232), TYTYTYEW (SEQ ID NO;

     233), VFTYTYEF (SEQ ID NO;

     234), AYTYEW (SEQ ID NO;

     235), DYIYTY (SEQ ID NO;

     236), IHSYEF (SEQ ID NO;

     237), SFTYEF (SEQ ID NO;

     238), SHSYEF (SEQ ID NO;

     239), THTYEF (SEQ ID NO;

     240), TWTYEF (SEQ ID NO;

     241), TYNYEW (SEQ ID NO;

     242), TYSYEF (SEQ ID NO;

     243), TYSYEH (SEQ ID NO;

     244), TYTYDF (SEQ ID NO;

     245), TYTYEF (SEQ ID NO;

     246), TYTYEW (SEQ ID NO;

     247), AYEF (SEQ ID NO;

     248), AYSF (SEQ ID NO;

     249), AYSY (SEQ ID NO;

     250), CYSF (SEQ ID NO;

     251), DYTY (SEQ ID NO;

     252), KYEH (SEQ ID NO;

     253), KYEW (SEQ ID NO;

     254), MYEF (SEQ ID NO;

     255), NWIY (SEQ ID NO;

     256), NYDY (SEQ ID NO;

     257), NYQW (SEQ ID NO;

     258), NYSF (SEQ ID NO;

     259), PYEW (SEQ ID NO;

     260), RYNW (SEQ ID NO;

     261), RYTY (SEQ ID NO;

     262), SYEF (SEQ ID NO;

     263), SYEH (SEQ ID NO;

     264), SYEW (SEQ ID NO;

     265), SYKW (SEQ ID NO;

     266), SYTY (SEQ ID NO;

     267), TYDF (SEQ ID NO;

     268), TYEF (SEQ ID NO;

     269), TYEW (SEQ ID NO;

     270), TYQW (SEQ ID NO;

     271), TYTY (SEQ ID NO;

     272), or VYEW (SEQ ID NO;

     273).

106. The library of claim 104, wherein the (X^aX^b)_z motif is YXYXYX.

107. The library of claim 76, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵X_n motif, wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q), and wherein n is 27-54.

108. The library of claim 76, wherein the ultralong CDR3 comprises X_n(X^aX^b)_z motif, wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), wherein n is 27-54, and wherein z is 1-4.

109. The library of claim 76, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵X_n(X^aX^b)_z motif,

wherein X₁ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X₂ is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X₃ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X₄ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), wherein X₅ is glutamine (Q), X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), wherein n is 27-54, and wherein z is 1-4.

110. The library of claim 109, wherein the X¹X²X³X⁴X⁵ motif is TTVHQ (SEQ ID NO:

153) or TSVHQ (SEQ ID NO;

     154), and wherein the (X^aX^b)_z motif is YXYXYX.

111. The library of claim 76, wherein the ultralong CDR3 comprises:

a CX¹X²X³X⁴X⁵ motif, wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q),

a cysteine motif selected from the group consisting of;

CX₁₀CX₅CX₅CXCX₇C (SEQ ID NO;

     41), CX₁₀CX₆CX₅CXCX₁₅C (SEQ ID NO;

     42), CX₁₁CXCX₅C (SEQ ID NO;

     43), CX₁₁CX₅CX₅CXCX₇C (SEQ ID NO;

     44), CX₁₀CX₆CX₅CXCX₁₃C (SEQ ID NO;

     45), CX₁₀CX₅CXCX₄CX₈C (SEQ ID NO;

     46), CX₁₀CX₆CX₆CXCX₇C (SEQ ID NO;

     47), CX₁₀CX₄CX₇CXCX₈C (SEQ ID NO;

     48), CX₁₀CX₄CX₇CXCX₇C (SEQ ID NO;

     49), CX₁₃CX₈CX₈C (SEQ ID NO;

     50), CX₁₀CX₆CX₅CXCX₇C (SEQ ID NO;

     51), CX₁₀CX₅CX₅C (SEQ ID NO;

     52), CX₁₀CX₅CX₆CXCX₇C (SEQ ID NO;

     53), CX₁₀CX₆CX₅CX₇CX₈C (SEQ ID NO;

     54), CX₉CX₇CX₅CXCX₇C (SEQ ID NO;

     55), CX₁₀CX₆CX₅CXCX₈C (SEQ ID NO;

     56), CX₁₀CXCX₄CX₅CX₁₁C (SEQ ID NO;

     57), CX₇CX₃CX₆CX₅CXCX₅CX₁₀C (SEQ ID NO;

     58), CX₁₀CXCX₄CX₅CXCX₂CX₃C (SEQ ID NO;

     59), CX₁₆CX₅CXC (SEQ ID NO;

     60), CX₆CX₄CXCX₄CX₅C (SEQ ID NO;

     61), CX₁₁CX₄CX₅CX₆CX₃C (SEQ ID NO;

     62), CX₈CX₂CX₆CX₅C (SEQ ID NO;

     63), CX₁₀CX₅CX₅CXCX₁₀C (SEQ ID NO;

     64), CX₁₀CXCX₆CX₄CXC (SEQ ID NO;

     65), CX₁₀CX₅CX₅CXCX₂C (SEQ ID NO;

     66), CX₁₄CX₂CX₃CXCXC (SEQ ID NO;

     67), CX₁₅CX₅CXC (SEQ ID NO;

     68), CX₄CX₆CX₉CX₂CX₁₁C (SEQ ID NO;

     69), CX₆CX₄CX₅CX₅CX₁₂C (SEQ ID NO;

     70), CX₇CX₃CXCXCX₄CX₅CX₉C (SEQ ID NO;

     71), CX₁₀CX₆CX₅C (SEQ ID NO;

     72), CX₇CX₃CX₅CX₅CX₉C (SEQ ID NO;

     73), CX₇CX₅CXCX₂C (SEQ ID NO;

     74), CX₁₀CXCX₆C (SEQ ID NO;

     75), CX₁₀CX₃CX₃CX₅CX₇CXCX₆C (SEQ ID NO;

     76), CX₁₀CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     77), CX₁₂CX₄CX₅CXCXCX₉CX₃C (SEQ ID NO;

     78), CX₁₂CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     79), CX₁₀CX₆CX₅CXCX₁₁C (SEQ ID NO;

     80), CX₁₆CX₅CXCXCX₁₄C (SEQ ID NO;

     81), CX₁₀CX₅CXCX₈CX₆C (SEQ ID NO;

     82), CX₁₂CX₄CX₅CX₈CX₂C (SEQ ID NO;

     83), CX₁₂CX₅CX₅CXCX₈C (SEQ ID NO;

     84), CX₁₀CX₆CX₅CXCX₄CXCX₈C (SEQ ID NO;

     85), CX₁₁CX₄CX₅CX₈CX₂C (SEQ ID NO;

     86), CX₁₀CX₆CX₅CX₈CX₂C (SEQ ID NO;

     87), CX₁₀CX₆CX₅CXCX₈C (SEQ ID NO;

     88), CX₁₀CX₆CX₅CXCX₃CX₈CX₂C (SEQ ID NO;

     89), CX₁₀CX₆CX₅CX₃CX₈C (SEQ ID NO;

     90), CX₁₀CX₆CX₅CXCX₂CX₆CX₅C (SEQ ID NO;

     91), CX₇CX₆CX₃CX₃CX₉C (SEQ ID NO;

     92), CX₉CX₈CX₅CX₆CX₅C (SEQ ID NO;

     93), CX₁₀CX₂CX₂CX₇CXCX₁₁CX₅C (SEQ ID NO;

     94), and CX₁₀CX₆CX₅CXCX₂CX₈CX₄C (SEQ ID NO;

     95), and

a (X^aX^b)_z motif, X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of;

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein z is 1-4.

112. The library of claim 76, wherein the ultralong CDR3 comprises:

a CX¹X²X³X⁴X⁵ motif, wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q);

a cysteine motif selected from the group consisting of;

wherein the cysteine motif is selected from the group consisting of;

CCX₃CXCX₃CX₂CCXCX₅CX₉CX₅CXC (SEQ ID NO;

     96), CX₆CX₂CX₅CX₄CCXCX₄CX₆CXC (SEQ ID NO;

     97), CX₇CXCX₅CX₄CCCX₄CX₆CXC (SEQ ID NO;

     98), CX₉CX₃CXCX₂CXCCCX₆CX₄C (SEQ ID NO;

     99), CX₅CX₃CXCX₄CX₄CCX₁₀CX₂CC (SEQ ID NO;

     100), CX₅CXCX₁CXCX₃CCX₃CX₄CX₁₀C (SEQ ID NO;

     101), CX₉CCCX₃CX₄CCCX₅CX₆C (SEQ ID NO;

     102), CCX₈CX₅CX₄CX₃CX₄CCXCX₁C (SEQ ID NO;

     103), CCX₆CCX₅CCCX₄CX₄CX₁₂C (SEQ ID NO;

     104), CX₆CX₂CX₃CCCX₄CX₅CX₃CX₃C (SEQ ID NO;

     105), CX₃CX₅CX₆CX₄CCXCX₅CX₄CXC (SEQ ID NO;

     106), CX₄CX₄CCX₄CX₄CXCX₁₁CX₂CXC (SEQ ID NO;

     107), CX₅CX₂CCX₅CX₄CCX₃CCX₇C (SEQ ID NO;

     108), CX₅CX₅CX₃CX₂CXCCX₄CX₇CXC (SEQ ID NO;

     109), CX₃CX₇CX₃CX₄CCXCX₂CX₅CX₂C (SEQ ID NO;

     110), CX₉CX₃CXCX₄CCX₅CCCX₆C (SEQ ID NO;

     111), CX₉CX₃CXCX₂CXCCX₆CX₃CX₃C (SEQ ID NO;

     112), CX₈CCXCX₃CCX₃CXCX₃CX₄C (SEQ ID NO;

     113), CX₉CCX₄CX₂CXCCXCX₄CX₃C (SEQ ID NO;

     114), CX₁₀CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     115), CX₉CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     116), CX₆CCXCX₅CX₄CCXCX₅CX₂C (SEQ ID NO;

     117), CX₆CCXCX₃CXCCX₃CX₄CC (SEQ ID NO;

     118), CX₆CCXCX₃CXCX₂CXCX₄CX₈C (SEQ ID NO;

     119), CX₄CX₂CCX₃CXCX₄CCX₂CX₃C (SEQ ID NO;

     120), CX₃CX₅CX₃CCCX₄CX₉C (SEQ ID NO;

     121), CCX₉CX₃CXCCX₃CX₅C (SEQ ID NO;

     122), CX₉CX₂CX₃CX₄CCX₄CX₅C (SEQ ID NO;

     123), CX₉CX₇CX₄CCXCX₇CX₃C (SEQ ID NO;

     124), CX₉CX₃CCCX₁₀CX₂CX₃C (SEQ ID NO;

     125), CX₃CX₅CX₅CX₄CCX₁₀CX₆C (SEQ ID NO;

     126), CX₉CX₅CX₄CCXCX₅CX₄C (SEQ ID NO;

     127), CX₇CXCX₆CX₄CCCX₁₀C (SEQ ID NO;

     128), CX₈CX₂CX₄CCX₄CX₃CX₃C (SEQ ID NO;

     129), CX₇CX₅CXCX₄CCX₇CX₄C (SEQ ID NO;

     130), CX₁₁CX₃CX₄CCCX₈CX₂C (SEQ ID NO;

     131), CX₂CX₃CX₄CCX₄CX₅CX₁₅C (SEQ ID NO;

     132), CX₉CX₅CX₄CCX₇C (SEQ ID NO;

     133), CX₉CX₇CX₃CX₂CX₆C (SEQ ID NO;

     134), CX₉CX₅CX₄CCX₁₄C (SEQ ID NO;

     135), CX₉CX₆CX₄CCX₈C (SEQ ID NO;

     136), CX₉CX₆CX₄CCXC (SEQ ID NO;

     137), CX₅CCX₇CX₄CX₁₂ (SEQ ID NO;

     138), CX₁₀CX₃CX₄CCX₄C (SEQ ID NO;

     139), CX₉CX₄CCX₅CX₄C (SEQ ID NO;

     140), CX₁₀CX₃CX₄CX₇CXC (SEQ ID NO;

     141), CX₇CX₇CX₂CX₂CX₃C (SEQ ID NO;

     142), CX₉CX₄CX₄CCX₆C (SEQ ID NO;

     143), CX₇CXCX₃CXCX₆C (SEQ ID NO;

     144), CX₇CXCX₄CXCX₄C (SEQ ID NO;

     145), CX₉CX₅CX₄C (SEQ ID NO;

     146), CX₃CX₆CX₈C (SEQ ID NO;

     147), CX₁₀CXCX₄C (SEQ ID NO;

     148), CX₁₀CCX₄C (SEQ ID NO;

     149), CX₁₅C (SEQ ID NO;

     150), CX₁₀C (SEQ ID NO;

     151), and CX₉C (SEQ ID NO;

     152); and

a (X^aX^b)_z motif, wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of;

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein z is 1-4.

113. The library of claim 95, wherein the ultralong CDR3 comprises an additional sequence that is a linker.

114. The library of claim 113, wherein the linker is linked to a C-terminus, a N-terminus, or both C-terminus and N-terminus of the non-antibody sequence.

115. The library of claim 76, wherein the ultralong CDR3 is a ruminant CDR3.

116. The library of claim 115, wherein the ruminant is a cow.

118. The library of claim 76, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

739.

119. The library of claim 76, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

741.

120. The library of claim 76, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

743.

121. The library of claim 76, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

745.

122. The library of claim 76, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

747.

123. The library of claim 76, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:

749.

124. The library of claim 76, wherein the ultralong CDR3 comprises an amino acid sequence of:

(i) any one of GSKHRLRDYFLYNE (SEQ ID NO;

     501), GSKHRLRDYFLYN (SEQ ID NO;

     502), GSKHRLRDYFLY (SEQ ID NO;

     503), GSKHRLRDYFL (SEQ ID NO;

     504), GSKHRLRDYF (SEQ ID NO;

     505), GSKHRLRDY (SEQ ID NO;

     506), or GSKHRLRD (SEQ ID NO;

     507);

(ii) any one of EAGGPDYRNGYNY (SEQ ID NO;

     508), EAGGPDYRNGYN (SEQ ID NO;

     509), EAGGPDYRNGY (SEQ ID NO;

     510), EAGGPDYRNG (SEQ ID NO;

     511), EAGGPDYRN (SEQ ID NO;

     512), EAGGPDYR (SEQ ID NO;

     513), EAGGPDY (SEQ ID NO;

     514), or EAGGPD (SEQ ID NO;

     515);

(iii) any one of EAGGPIWHDDVKY (SEQ ID NO;

     516), EAGGPIWHDDVK (SEQ ID NO;

     517), EAGGPIWHDDV (SEQ ID NO;

     518), EAGGPIWHDD (SEQ ID NO;

     519), EAGGPIWHD (SEQ ID NO;

     520), EAGGPIWH (SEQ ID NO;

     521), EAGGPIW (SEQ ID NO;

     522), or EAGGPI (SEQ ID NO;

     523);

(iv) any one of GTDYTIDDQGI (SEQ ID NO;

     524), GTDYTIDDQG (SEQ ID NO;

     525), GTDYTIDDQ (SEQ ID NO;

     526), GTDYTIDD (SEQ ID NO;

     527), GTDYTID (SEQ ID NO;

     528), or GTDYTI (SEQ ID NO;

     529);

(v) any one of DKGDSDYDYNL (SEQ ID NO;

     530), DKGDSDYDYN (SEQ ID NO;

     531), DKGDSDYDY (SEQ ID NO;

     532), DKGDSDYD (SEQ ID NO;

     533), DKGDSDY (SEQ ID NO;

     534), DKGDSD (SEQ ID NO;

     535);

or

(vi) TSVHQETKKYQS (SEQ ID NO;

     498).

125. The library of claim 76, wherein the ultralong CDR3 comprises an amino acid sequence of:

(i) any one of YGPNYEEWGDYLATLDV (SEQ ID NO;

     536), GPNYEEWGDYLATLDV (SEQ ID NO;

     537), PNYEEWGDYLATLDV (SEQ ID NO;

     538), NYEEWGDYLATLDV (SEQ ID NO;

     539), YEEWGDYLATLDV (SEQ ID NO;

     540), or EEWGDYLATLDV (SEQ ID NO;

     541);

(ii) any one of YDFYDGYYNYHYMDV (SEQ ID NO;

     542), DFYDGYYNYHYMDV (SEQ ID NO;

     543), FYDGYYNYHYMDV (SEQ ID NO;

     544), YDGYYNYHYMDV (SEQ ID NO;

     545), DGYYNYHYMDV (SEQ ID NO;

     546), GYYNYHYMDV (SEQ ID NO;

     547), or YYNYHYMDV (SEQ ID NO;

     548);

(iii) any one of YDFNDGYYNYHYMDV (SEQ ID NO;

     549), DFYDGYYNYHYMDV (SEQ ID NO;

     550), FYDGYYNYHYMDV (SEQ ID NO;

     551), YDGYYNYHYMDV (SEQ ID NO;

     552), DGYYNYHYMDV (SEQ ID NO;

     553), or GYYNYHYMDV (SEQ ID NO;

     554);

(iv) any one of QGIRYQGSGTFWYFDV (SEQ ID NO;

     555), GIRYQGSGTFWYFDV (SEQ ID NO;

     556), IRYQGSGTFWYFDV (SEQ ID NO;

     557), RYQGSGTFWYFDV (SEQ ID NO;

     558), YQGSGTFWYFDV (SEQ ID NO;

     559), QGSGTFWYFDV (SEQ ID NO;

     560), GSGTFWYFDV (SEQ ID NO;

     561), SGTFWYFDV (SEQ ID NO;

     562), or GTFWYFDV (SEQ ID NO;

     563);

(v) any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569);

or

(vi) SYTYNYEWHVDV (SEQ ID NO;

     499).

126. The library of claim 76, wherein the humanized antibody or binding fragment thereof comprises a light chain variable region comprising a sequence selected from the group of:

(i) SEQ ID NO;

750, (ii) SEQ ID NO;

751, (iii) SEQ ID NO;

752, and (iv) SEQ ID NO;

753.

127. The library of claim 126, wherein the light chain variable region comprises a lambda light chain variable region sequence.

128. The library of claim 126, wherein the light chain variable region sequence comprises a human lambda light chain variable region sequence.

129. The library of claim 126, wherein the light chain variable region sequence comprises a VL1-51 germline sequence.

130. The library of claim 126, wherein the light chain variable region is derived from a VL1-51 germline sequence.

131. The library of claim 130, wherein the VL1-51 germline sequence comprises a CDR1 comprising Ile29Val and Asn32Gly substitution based on Kabat numbering.

132. The library of claim 130, wherein the VL1-51 germline sequence comprises a CDR2 comprising a substitution of DNN to GDT.

133. The library of claim 130, wherein the VL1-51 germline sequence comprises a CDR2 comprising a substitution of DNNKRP (SEQ ID NO:

471) to GDTSRA (SEQ ID NO;

     472).

134. The library of claim 130, wherein the VL1-51 germline sequence comprises a S2A, T5N, P8S, A12G, A13S, and P14L substitution based on Kabat numbering.

135. The library of claim 130, wherein the VL1-51 germline sequence comprises a S2A, T5N, P8S, A12G, A13S, and P14L substitution based on Kabat numbering, and a CDR2 comprising a substitution of DNN to GDT.

136. The library of claim 76, wherein the humanized antibody or binding fragment thereof comprising (a) a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NO:

740, SEQ ID NO;

741, SEQ ID NO;

742, and SEQ ID NO;

743; and

(b) a light chain variable region comprising SEQ ID NO;

750.

137. The library of any one of claims 76-136, wherein the humanized antibodies or binding fragments thereof are present in a spatially addressed format.

138. A method of humanizing an antibody variable region comprising the step of genetically combining a nucleic acid sequence encoding an ultralong CDR3 with a nucleic acid sequence encoding a variable region sequence selected from the group consisting of:

(i) SEQ ID NO;

734 or SEQ ID NO;

735,

(ii) SEQ ID NO;

736 or SEQ ID NO;

737,

(iii) SEQ ID NO;

738 or SEQ ID NO;

739,

(iv) SEQ ID NO;

740 or SEQ ID NO;

741,

(v) SEQ ID NO;

742 or SEQ ID NO;

743,

(vi) SEQ ID NO;

744 or SEQ ID NO;

745,

(vii) SEQ ID NO;

746 or SEQ ID NO;

747, and

(viii) SEQ ID NO;

748 or SEQ ID NO;

749.

139. A method of generating a library of humanized antibodies that comprises an ultralong CDR3, the method comprising:

a.) combining a nucleic acid sequence encoding an ultralong CDR3 with a nucleic acid sequence encoding a variable region sequence selected from the group consisting of;

(i) SEQ ID NO;

734 or SEQ ID NO;

735,

(ii) SEQ ID NO;

736 or SEQ ID NO;

737,

(iii) SEQ ID NO;

738 or SEQ ID NO;

739,

(iv) SEQ ID NO;

740 or SEQ ID NO;

741,

(v) SEQ ID NO;

742 or SEQ ID NO;

743,

(vi) SEQ ID NO;

744 or SEQ ID NO;

745,

(vii) SEQ ID NO;

746 or SEQ ID NO;

747, and

(viii) SEQ ID NO;

748 or SEQ ID NO;

749,

to produce nucleic acids encoding for humanized antibodies that comprises an ultralong CDR3; and

b.) expressing the nucleic acids encoding for humanized antibodies that comprises an ultralong CDR3 to generate a library of humanized antibodies that comprises an ultralong CDR3.

140. A method of generating a library of humanized antibodies or binding fragments thereof comprising an ultralong CDR3 that comprises a non-antibody sequence, the method comprising:

a.) combining a nucleic acid sequence encoding an ultralong CDR3, a nucleic acid sequence encoding a variable region sequence selected from the group consisting of;

(i) SEQ ID NO;

734 or SEQ ID NO;

735,

(ii) SEQ ID NO;

736 or SEQ ID NO;

737,

(iii) SEQ ID NO;

738 or SEQ ID NO;

739,

(iv) SEQ ID NO;

740 or SEQ ID NO;

741,

(v) SEQ ID NO;

742 or SEQ ID NO;

743,

(vi) SEQ ID NO;

744 or SEQ ID NO;

745,

(vii) SEQ ID NO;

746 or SEQ ID NO;

747, and

(viii) SEQ ID NO;

748 or SEQ ID NO;

749,

and a nucleic acid sequence encoding a non-antibody sequence to produce nucleic acids encoding humanized antibodies or binding fragments thereof comprising an ultralong CDR3 and a non-antibody sequence, and

b.) expressing the nucleic acids encoding humanized antibodies or binding fragments thereof comprising an ultralong CDR3 and a non-antibody sequence to generate a library of humanized antibodies or binding fragments thereof comprising an ultralong CDR3 and a non-antibody sequence.

141. A library of humanized antibodies or binding fragments thereof comprising an ultralong CDR3 that comprises a non-antibody sequence.

142. A method of generating a library of humanized antibodies or binding fragments thereof comprising an ultralong CDR3 that comprises a cysteine motif, the method comprising:

a.) combining a human variable region framework (FR) sequence, and a nucleic acid sequence encoding an ultralong CDR3 and a cysteine motif;

b.) introducing one or more nucleotide changes to the nucleic acid sequence encoding one or more amino acid residues that are positioned between one or more cysteine residues in the cysteine motif for nucleotides encoding different amino acid residues to produce nucleic acids encoding humanized antibodies or binding fragments thereof comprising an ultralong CDR3 and a cysteine motif with one or more nucleotide changes introduced between one or more cysteine residues in the cysteine domain; and

c.) expressing the nucleic acids encoding humanized antibodies or binding fragments thereof comprising an ultralong CDR3 and a cysteine motif with one or more nucleotide changes introduced between one or more cysteine residues in the cysteine domain to generate a library of humanized antibodies or binding fragments thereof comprising an ultralong CDR3 and a cysteine motif with one or more amino acid changes introduced between one or more cysteine residues in the cysteine domain.

180. The antibody heavy chain variable region of any one of claims 142-172, wherein the ultralong CDR3 comprises a linker sequence.

181. The antibody heavy chain variable region of claim 180, wherein the linker is linked to a N-terminus, a C-terminus, or both N-terminus and C-terminus of the non-antibody sequence.

182. The antibody heavy chain variable region of claim 180 or 181, wherein the linker comprises one or more amino acid sequence selected from the group consisting of SEQ ID NO:

575 to 598, 699 to 726 and 813 to 830, or any combination thereof.

183. The antibody heavy chain variable region of claim 181, wherein the linkers linked to both N-terminus and C-terminus have the same or different amino acid sequence.

212. The antibody heavy chain variable region of claim 211, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵X_n(X^aX^b)_z motif,

wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q), wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), wherein n is 27-54, and wherein z is 1-4. 206.) The antibody heavy chain variable region of any one of claims 142 to 145, wherein V1 comprises an amino acid sequence of SEQ ID NO;

737, wherein the ultralong CDR3 comprises an amino acid sequence of SEQ ID NO;

498 and SEQ ID NO;

499, and wherein V2 comprises an amino acid sequence of SEQ ID NO;

500.

143. A library of humanized antibodies or binding fragments thereof comprising an ultralong CDR3 that comprises a cysteine motif, wherein the antibodies or binding fragments comprise one or more substitutions of amino acid residues that are positioned between cysteine residues in the cysteine motif.

144. A method of generating a library of humanized antibodies or binding fragments thereof comprising a bovine ultralong CDR3, the method comprising:

a.) combining a nucleic acid sequence encoding a human variable region framework (FR) sequence and a nucleic acid encoding a bovine ultralong CDR3, and

b.) expressing the nucleic acids encoding a human variable region framework (FR) sequence and a nucleic acid encoding a bovine ultralong CDR3 to generate a library of humanized antibodies or binding fragments thereof comprising a bovine ultralong CDR3.

145. A library of humanized antibodies or binding fragments thereof comprising a heavy chain variable region comprising:

(a) an amino acid sequence selected from the group consisting of;

(i) SEQ ID NO;

734 or SEQ ID NO;

735,

(ii) SEQ ID NO;

736 or SEQ ID NO;

737,

(iii) SEQ ID NO;

738 or SEQ ID NO;

739,

(iv) SEQ ID NO;

740 or SEQ ID NO;

741,

(v) SEQ ID NO;

742 or SEQ ID NO;

743,

(vi) SEQ ID NO;

744 or SEQ ID NO;

745,

(vii) SEQ ID NO;

746 or SEQ ID NO;

747, and

(viii) SEQ ID NO;

748 or SEQ ID NO;

749; and

(b) a bovine ultralong CDR3.

146. An antibody heavy chain variable region comprising a sequence of the formula V1-X-V2, wherein V1 comprises an amino acid sequence selected from the group consisting of:

(i) QVQLREWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHS GSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     735),

(ii) QVQLREWGAGLLKPSETLSLTCAVYGGSFSDKYWSWIRQPPGKGLEWIGEINH SGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     737),

(iii) QVQLREWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGSINH SGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     739),

(iv) QVQLREWGAGLLKPSETLSLTCAVYGGSFSDKYWSWIRQPPGKGLEWIGSINH SGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     741),

(v) QVQLREWGAGLLKPSETLSLTCTASGFSLSDKAVGWIRQPPGKGLEWIGEINHS GSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     743),

(vi) QVQLREWGAGLLKPSETLSLTCAVYGGLGSIDTGGNTGSFSGYYWSWIRQPPG KGLEWYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     745),

(vii) QVQLREWGAGLLKPSETLSLTCTASGFSLSDKAVGWIRQPPGKGLEWIGSINH SGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     747), and

(viii) QVQLREWGAGLLKPSETLSLTCTASGFSLSDKAVGWIRQPPGKGLEWLGSIDT GGNTGYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     749);

wherein X comprises an ultralong CDR3; and

wherein V2 comprises an amino acid sequence selected from the group consisting of;

(i) WGHGTAVTVSS (SEQ ID NO;

     570),

(ii) WGKGTTVTVSS (SEQ ID NO;

     571),

(iii) WGKGTTVTVSS (SEQ ID NO;

     572),

(iv) WGRGTLVTVSS (SEQ ID NO;

     573),

(v) WGKGTTVTVSS (SEQ ID NO;

     574), and

(vi) WGQGLLVTVSS (SEQ ID NO;

     500).

147. ). The antibody heavy chain variable region of claim 146, wherein the ultralong CDR3 comprises an amino acid sequence of:

(i) any one of GSKHRLRDYFLYNE (SEQ ID NO;

     501), GSKHRLRDYFLYN (SEQ ID NO;

     502), GSKHRLRDYFLY (SEQ ID NO;

     503), GSKHRLRDYFL (SEQ ID NO;

     504), GSKHRLRDYF (SEQ ID NO;

     505), GSKHRLRDY (SEQ ID NO;

     506), or GSKHRLRD (SEQ ID NO;

     507);

(ii) any one of EAGGPDYRNGYNY (SEQ ID NO;

     508), EAGGPDYRNGYN (SEQ ID NO;

     509), EAGGPDYRNGY (SEQ ID NO;

     510), EAGGPDYRNG (SEQ ID NO;

     511), EAGGPDYRN (SEQ ID NO;

     512), EAGGPDYR (SEQ ID NO;

     513), EAGGPDY (SEQ ID NO;

     514), or EAGGPD (SEQ ID NO;

     515);

(iii) any one of EAGGPIWHDDVKY (SEQ ID NO;

     516), EAGGPIWHDDVK (SEQ ID NO;

     517), EAGGPIWHDDV (SEQ ID NO;

     518), EAGGPIWHDD (SEQ ID NO;

     519), EAGGPIWHD (SEQ ID NO;

     520), EAGGPIWH (SEQ ID NO;

     521), EAGGPIW (SEQ ID NO;

     522), or EAGGPI (SEQ ID NO;

     523);

(iv) any one of GTDYTIDDQGI (SEQ ID NO;

     524), GTDYTIDDQG (SEQ ID NO;

     525), GTDYTIDDQ (SEQ ID NO;

     526), GTDYTIDD (SEQ ID NO;

     527), GTDYTID (SEQ ID NO;

     528), or GTDYTI (SEQ ID NO;

     529);

(v) any one of DKGDSDYDYNL (SEQ ID NO;

     530), DKGDSDYDYN (SEQ ID NO;

     531), DKGDSDYDY (SEQ ID NO;

     532), DKGDSDYD (SEQ ID NO;

     533), DKGDSDY (SEQ ID NO;

     534), DKGDSD (SEQ ID NO;

     535);

or

(vi) TSVHQETKKYQS (SEQ ID NO;

     498).

148. The antibody heavy chain variable region of claim 146, wherein the ultralong CDR3 comprises an amino acid sequence of:

(i) any one of YGPNYEEWGDYLATLDV (SEQ ID NO;

     536), GPNYEEWGDYLATLDV (SEQ ID NO;

     537), PNYEEWGDYLATLDV (SEQ ID NO;

     538), NYEEWGDYLATLDV (SEQ ID NO;

     539), YEEWGDYLATLDV (SEQ ID NO;

     540), or EEWGDYLATLDV (SEQ ID NO;

     541);

(ii) any one of YDFYDGYYNYHYMDV (SEQ ID NO;

     542), DFYDGYYNYHYMDV (SEQ ID NO;

     543), FYDGYYNYHYMDV (SEQ ID NO;

     544), YDGYYNYHYMDV (SEQ ID NO;

     545), DGYYNYHYMDV (SEQ ID NO;

     546), GYYNYHYMDV (SEQ ID NO;

     547), or YYNYHYMDV (SEQ ID NO;

     548);

(iii) any one of YDFNDGYYNYHYMDV (SEQ ID NO;

     549), DFYDGYYNYHYMDV (SEQ ID NO;

     550), FYDGYYNYHYMDV (SEQ ID NO;

     551), YDGYYNYHYMDV (SEQ ID NO;

     552), DGYYNYHYMDV (SEQ ID NO;

     553), or GYYNYHYMDV (SEQ ID NO;

     554);

(iv) any one of QGIRYQGSGTFWYFDV (SEQ ID NO;

     555), GIRYQGSGTFWYFDV (SEQ ID NO;

     556), IRYQGSGTFWYFDV (SEQ ID NO;

     557), RYQGSGTFWYFDV (SEQ ID NO;

     558), YQGSGTFWYFDV (SEQ ID NO;

     559), QGSGTFWYFDV (SEQ ID NO;

     560), GSGTFWYFDV (SEQ ID NO;

     561), SGTFWYFDV (SEQ ID NO;

     562), or GTFWYFDV (SEQ ID NO;

     563);

(v) any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569);

or

(vi) SYTYNYEWHVDV (SEQ ID NO;

     499).

149. The antibody heavy chain variable region of claim 146, wherein the ultralong CDR3 comprises an amino acid sequence of:

(i) any one of GSKHRLRDYFLYNE (SEQ ID NO;

     501), GSKHRLRDYFLYN (SEQ ID NO;

     502), GSKHRLRDYFLY (SEQ ID NO;

     503), GSKHRLRDYFL (SEQ ID NO;

     504), GSKHRLRDYF (SEQ ID NO;

     505), GSKHRLRDY (SEQ ID NO;

     506), or GSKHRLRD (SEQ ID NO;

     507), and any one of YGPNYEEWGDYLATLDV (SEQ ID NO;

     536), GPNYEEWGDYLATLDV (SEQ ID NO;

     537), PNYEEWGDYLATLDV (SEQ ID NO;

     538), NYEEWGDYLATLDV (SEQ ID NO;

     539), YEEWGDYLATLDV (SEQ ID NO;

     540), or EEWGDYLATLDV (SEQ ID NO;

     541);

(ii) any one of EAGGPDYRNGYNY (SEQ ID NO;

     508), EAGGPDYRNGYN (SEQ ID NO;

     509), EAGGPDYRNGY (SEQ ID NO;

     510), EAGGPDYRNG (SEQ ID NO;

     511), EAGGPDYRN (SEQ ID NO;

     512), EAGGPDYR (SEQ ID NO;

     513), EAGGPDY (SEQ ID NO;

     514), or EAGGPD (SEQ ID NO;

     515), and any one of YDFYDGYYNYHYMDV (SEQ ID NO;

     542), DFYDGYYNYHYMDV (SEQ ID NO;

     543), FYDGYYNYHYMDV (SEQ ID NO;

     544), YDGYYNYHYMDV (SEQ ID NO;

     545), DGYYNYHYMDV (SEQ ID NO;

     546), GYYNYHYMDV (SEQ ID NO;

     547), or YYNYHYMDV (SEQ ID NO;

     548);

(iii) any one of EAGGPIWHDDVKY (SEQ ID NO;

     516), EAGGPIWHDDVK (SEQ ID NO;

     517), EAGGPIWHDDV (SEQ ID NO;

     518), EAGGPIWHDD (SEQ ID NO;

     519), EAGGPIWHD (SEQ ID NO;

     520), EAGGPIWH (SEQ ID NO;

     521), EAGGPIW (SEQ ID NO;

     522), or EAGGPI (SEQ ID NO;

     523), and any one of YDFNDGYYNYHYMDV (SEQ ID NO;

     549), DFYDGYYNYHYMDV (SEQ ID NO;

     550), FYDGYYNYHYMDV (SEQ ID NO;

     551), YDGYYNYHYMDV (SEQ ID NO;

     552), DGYYNYHYMDV (SEQ ID NO;

     553), or GYYNYHYMDV (SEQ ID NO;

     554);

(iv) any one of GTDYTIDDQGI (SEQ ID NO;

     524), GTDYTIDDQG (SEQ ID NO;

     525), GTDYTIDDQ (SEQ ID NO;

     526), GTDYTIDD (SEQ ID NO;

     527), GTDYTID (SEQ ID NO;

     528), or GTDYTI (SEQ ID NO;

     529), and any one of QGIRYQGSGTFWYFDV (SEQ ID NO;

     555), GIRYQGSGTFWYFDV (SEQ ID NO;

     556), IRYQGSGTFWYFDV (SEQ ID NO;

     557), RYQGSGTFWYFDV (SEQ ID NO;

     558), YQGSGTFWYFDV (SEQ ID NO;

     559), QGSGTFWYFDV (SEQ ID NO;

     560), GSGTFWYFDV (SEQ ID NO;

     561), SGTFWYFDV (SEQ ID NO;

     562), or GTFWYFDV (SEQ ID NO;

     563);

(v) any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569), and any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569);

or

(vi) TSVHQETKKYQS (SEQ ID NO;

     498) and SYTYNYEWHVDV (SEQ ID NO;

     499).

150. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of GSKHRLRDYFLYNE (SEQ ID NO;

     501), GSKHRLRDYFLYN (SEQ ID NO;

     502), GSKHRLRDYFLY (SEQ ID NO;

     503), GSKHRLRDYFL (SEQ ID NO;

     504), GSKHRLRDYF (SEQ ID NO;

     505), GSKHRLRDY (SEQ ID NO;

     506), or GSKHRLRD (SEQ ID NO;

     507), and an amino acid sequence of any one of YGPNYEEWGDYLATLDV (SEQ ID NO;

     536), GPNYEEWGDYLATLDV (SEQ ID NO;

     537), PNYEEWGDYLATLDV (SEQ ID NO;

     538), NYEEWGDYLATLDV (SEQ ID NO;

     539), YEEWGDYLATLDV (SEQ ID NO;

     540), or EEWGDYLATLDV (SEQ ID NO;

     541),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

151. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of EAGGPDYRNGYNY (SEQ ID NO;

     508), EAGGPDYRNGYN (SEQ ID NO;

     509), EAGGPDYRNGY (SEQ ID NO;

     510), EAGGPDYRNG (SEQ ID NO;

     511), EAGGPDYRN (SEQ ID NO;

     512), EAGGPDYR (SEQ ID NO;

     513), EAGGPDY (SEQ ID NO;

     514), or EAGGPD (SEQ ID NO;

     515), and an amino acid sequence of any one of YDFYDGYYNYHYMDV (SEQ ID NO;

     542), DFYDGYYNYHYMDV (SEQ ID NO;

     543), FYDGYYNYHYMDV (SEQ ID NO;

     544), YDGYYNYHYMDV (SEQ ID NO;

     545), DGYYNYHYMDV (SEQ ID NO;

     546), GYYNYHYMDV (SEQ ID NO;

     547), or YYNYHYMDV (SEQ ID NO;

     548),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

152. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of EAGGPIWHDDVKY (SEQ ID NO;

     516), EAGGPIWHDDVK (SEQ ID NO;

     517), EAGGPIWHDDV (SEQ ID NO;

     518), EAGGPIWHDD (SEQ ID NO;

     519), EAGGPIWHD (SEQ ID NO;

     520), EAGGPIWH (SEQ ID NO;

     521), EAGGPIW (SEQ ID NO;

     522), or EAGGPI (SEQ ID NO;

     523), and an amino acid sequence of any one of YDFNDGYYNYHYMDV (SEQ ID NO;

     549), DFYDGYYNYHYMDV (SEQ ID NO;

     550), FYDGYYNYHYMDV (SEQ ID NO;

     551), YDGYYNYHYMDV (SEQ ID NO;

     552), DGYYNYHYMDV (SEQ ID NO;

     553), or GYYNYHYMDV (SEQ ID NO;

     554),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

153. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of GTDYTIDDQGI (SEQ ID NO;

     524), GTDYTIDDQG (SEQ ID NO;

     525), GTDYTIDDQ (SEQ ID NO;

     526), GTDYTIDD (SEQ ID NO;

     527), GTDYTID (SEQ ID NO;

     528), or GTDYTI (SEQ ID NO;

     529), and an amino acid sequence of any one of QGIRYQGSGTFWYFDV (SEQ ID NO;

     555), GIRYQGSGTFWYFDV (SEQ ID NO;

     556), IRYQGSGTFWYFDV (SEQ ID NO;

     557), RYQGSGTFWYFDV (SEQ ID NO;

     558), YQGSGTFWYFDV (SEQ ID NO;

     559), QGSGTFWYFDV (SEQ ID NO;

     560), GSGTFWYFDV (SEQ ID NO;

     561), SGTFWYFDV (SEQ ID NO;

     562), or GTFWYFDV (SEQ ID NO;

     563),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

154. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569), and any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

155. The antibody heavy chain variable region of any one of claims 146-154, wherein the ultralong CDR3 is 35 amino acids in length or longer, 40 amino acids in length or longer, 45 amino acids in length or longer, 50 amino acids in length or longer, 55 amino acids in length or longer, or 60 amino acids in length or longer.

156. The antibody heavy chain variable region of claim 155, wherein the ultralong CDR3 is 35 amino acids in length or longer.

157. The antibody heavy chain variable region of claim 146-156, wherein the ultralong CDR3 comprises a cysteine motif.

158. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of GSKHRLRDYFLYNE (SEQ ID NO;

     501), GSKHRLRDYFLYN (SEQ ID NO;

     502), GSKHRLRDYFLY (SEQ ID NO;

     503), GSKHRLRDYFL (SEQ ID NO;

     504), GSKHRLRDYF (SEQ ID NO;

     505), GSKHRLRDY (SEQ ID NO;

     506), or GSKHRLRD (SEQ ID NO;

     507), a cysteine motif, and an amino acid sequence of any one of YGPNYEEWGDYLATLDV (SEQ ID NO;

     536), GPNYEEWGDYLATLDV (SEQ ID NO;

     537), PNYEEWGDYLATLDV (SEQ ID NO;

     538), NYEEWGDYLATLDV (SEQ ID NO;

     539), YEEWGDYLATLDV (SEQ ID NO;

     540), or EEWGDYLATLDV (SEQ ID NO;

     541), and

wherein V2 comprises an amino acid sequence of WGQGLLVTVSS (SEQ ID NO;

     500).

159. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of EAGGPDYRNGYNY (SEQ ID NO;

     508), EAGGPDYRNGYN (SEQ ID NO;

     509), EAGGPDYRNGY (SEQ ID NO;

     510), EAGGPDYRNG (SEQ ID NO;

     511), EAGGPDYRN (SEQ ID NO;

     512), EAGGPDYR (SEQ ID NO;

     513), EAGGPDY (SEQ ID NO;

     514), or EAGGPD (SEQ ID NO;

     515), a cysteine motif, and an amino acid sequence of any one of YDFYDGYYNYHYMDV (SEQ ID NO;

     542), DFYDGYYNYHYMDV (SEQ ID NO;

     543), FYDGYYNYHYMDV (SEQ ID NO;

     544), YDGYYNYHYMDV (SEQ ID NO;

     545), DGYYNYHYMDV (SEQ ID NO;

     546), GYYNYHYMDV (SEQ ID NO;

     547), or YYNYHYMDV (SEQ ID NO;

     548),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

160. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of EAGGPIWHDDVKY (SEQ ID NO;

     516), EAGGPIWHDDVK (SEQ ID NO;

     517), EAGGPIWHDDV (SEQ ID NO;

     518), EAGGPIWHDD (SEQ ID NO;

     519), EAGGPIWHD (SEQ ID NO;

     520), EAGGPIWH (SEQ ID NO;

     521), EAGGPIW (SEQ ID NO;

     522), or EAGGPI (SEQ ID NO;

     523), a cysteine motif, and an amino acid sequence of any one of YDFNDGYYNYHYMDV (SEQ ID NO;

     549), DFYDGYYNYHYMDV (SEQ ID NO;

     550), FYDGYYNYHYMDV (SEQ ID NO;

     551), YDGYYNYHYMDV (SEQ ID NO;

     552), DGYYNYHYMDV (SEQ ID NO;

     553), or GYYNYHYMDV (SEQ ID NO;

     554),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

161. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of GTDYTIDDQGI (SEQ ID NO;

     524), GTDYTIDDQG (SEQ ID NO;

     525), GTDYTIDDQ (SEQ ID NO;

     526), GTDYTIDD (SEQ ID NO;

     527), GTDYTID (SEQ ID NO;

     528), or GTDYTI (SEQ ID NO;

     529), a cysteine motif, and an amino acid sequence of any one of QGIRYQGSGTFWYFDV (SEQ ID NO;

     555), GIRYQGSGTFWYFDV (SEQ ID NO;

     556), IRYQGSGTFWYFDV (SEQ ID NO;

     557), RYQGSGTFWYFDV (SEQ ID NO;

     558), YQGSGTFWYFDV (SEQ ID NO;

     559), QGSGTFWYFDV (SEQ ID NO;

     560), GSGTFWYFDV (SEQ ID NO;

     561), SGTFWYFDV (SEQ ID NO;

     562), or GTFWYFDV (SEQ ID NO;

     563),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

162. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569), a cysteine motif, and an amino acid sequence of any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

163. The antibody heavy claim variable region of claim 146,

wherein VI comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence that is SEQ ID NO;

498 and an amino acid sequence that is SEQ ID NO;

499,

wherein V2 comprises an amino acid sequence that is SEQ ID NO;

500.

164. The antibody heavy chain variable region of any one of claim 157-163, wherein the cysteine motif is selected from the group consisting of:

CX₁₀CX₅CX₅CXCX₇C (SEQ ID NO;

     41), CX₁₀CX₆CX₅CXCX₁₅C (SEQ ID NO;

     42), CX₁₁CXCX₅C (SEQ ID NO;

     43), CX₁₁CX₅CX₅CXCX₇C (SEQ ID NO;

     44), CX₁₀CX₆CX₅CXCX₁₃C (SEQ ID NO;

     45), CX₁₀CX₅CXCX₄CX₈C (SEQ ID NO;

     46), CX₁₀CX₆CX₆CXCX₇C (SEQ ID NO;

     47), CX₁₀CX₄CX₇CXCX₈C (SEQ ID NO;

     48), CX₁₀CX₄CX₇CXCX₇C (SEQ ID NO;

     49), CX₁₃CX₈CX₈C (SEQ ID NO;

     50), CX₁₀CX₆CX₅CXCX₇C (SEQ ID NO;

     51), CX₁₀CX₅CX₅C (SEQ ID NO;

     52), CX₁₀CX₅CX₆CXCX₇C (SEQ ID NO;

     53), CX₁₀CX₆CX₅CX₇CX₉C (SEQ ID NO;

     54), CX₉CX₇CX₅CXCX₇C (SEQ ID NO;

     55), CX₁₀CX₆CX₅CXCX₉C (SEQ ID NO;

     56), CX₁₀CXCX₄CX₅CX₁₁C (SEQ ID NO;

     57), CX₇CX₃CX₆CX₅CXCX₅CX₁₀C (SEQ ID NO;

     58), CX₁₀CXCX₄CX₅CXCX₂CX₃C (SEQ ID NO;

     59), CX₁₆CX₅CXC (SEQ ID NO;

     60), CX₆CX₄CXCX₄CX₅C (SEQ ID NO;

     61), CX₁₁CX₄CX₅CX₆CX₃C (SEQ ID NO;

     62), CX₈CX₂CX₆CX₅C (SEQ ID NO;

     63), CX₁₀CX₅CX₅CXCX₁₀C (SEQ ID NO;

     64), CX₁₀CXCX₆CX₄CXC (SEQ ID NO;

     65), CX₁₀CX₅CX₅CXCX₂C (SEQ ID NO;

     66), CX₁₄CX₂CX₃CXCXC (SEQ ID NO;

     67), CX₁₅CX₅CXC (SEQ ID NO;

     68), CX₄CX₆CX₉CX₂CX₁₁C (SEQ ID NO;

     69), CX₆CX₄CX₅CX₅CX₁₂C (SEQ ID NO;

     70), CX₇CX₃CXCXCX₄CX₅CX₉C (SEQ ID NO;

     71), CX₁₀CX₆CX₅C (SEQ ID NO;

     72), CX₇CX₃CX₅CX₅CX₉C (SEQ ID NO;

     73), CX₇CX₅CXCX₂C (SEQ ID NO;

     74), CX₁₀CXCX₆C (SEQ ID NO;

     75), CX₁₀CX₃CX₃CX₅CX₇CXCX₆C (SEQ ID NO;

     76), CX₁₀CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     77), CX₁₂CX₄CX₅CXCXCX₉CX₃C (SEQ ID NO;

     78), CX₁₂CX₄CX₅CX₁₂CX₂C (SEQ ID NO;

     79), CX₁₀CX₆CX₅CXCX₁₁C (SEQ ID NO;

     80), CX₁₆CX₅CXCXCX₁₄C (SEQ ID NO;

     81), CX₁₀CX₅CXCX₈CX₆C (SEQ ID NO;

     82), CX₁₂CX₄CX₅CX₈CX₂C (SEQ ID NO;

     83), CX₁₂CX₅CX₅CXCX₈C (SEQ ID NO;

     84), CX₁₀CX₆CX₅CXCX₄CXCX₉C (SEQ ID NO;

     85), CX₁₁CX₄CX₅CX₈CX₂C (SEQ ID NO;

     86), CX₁₀CX₆CX₅CX₈CX₂C (SEQ ID NO;

     87), CX₁₀CX₆CX₅CXCX₈C (SEQ ID NO;

     88), CX₁₀CX₆CX₅CXCX₃CX₈CX₂C (SEQ ID NO;

     89), CX₁₀CX₆CX₅CX₃CX₈C (SEQ ID NO;

     90), CX₁₀CX₆CX₅CXCX₂CX₆CX₅C (SEQ ID NO;

     91), CX₇CX₆CX₃CX₃CX₉C (SEQ ID NO;

     92), CX₉CX₈CX₅CX₆CX₅C (SEQ ID NO;

     93), CX₁₀CX₂CX₂CX₇CXCX₁₁CX₅C (SEQ ID NO;

     94), and CX₁₀CX₆CX₅CXCX₂CX₈CX₄C (SEQ ID NO;

     95).

165. The antibody heavy chain variable region of any one of claim 157-163, wherein the cysteine motif is selected from the group consisting of:

CCX₃CXCX₃CX₂CCXCX₅CX₉CX₅CXC (SEQ ID NO;

     96), CX₆CX₂CX₅CX₄CCXCX₄CX₆CXC (SEQ ID NO;

     97), CX₇CXCX₅CX₄CCCX₄CX₆CXC (SEQ ID NO;

     98), CX₉CX₃CXCX₂CXCCCX₆CX₄C (SEQ ID NO;

     99), CX₅CX₃CXCX₄CX₄CCX₁₀CX₂CC (SEQ ID NO;

     100), CX₅CXCX₁CXCX₃CCX₃CX₄CX₁₀C (SEQ ID NO;

     101), CX₉CCCX₃CX₄CCCX₅CX₆C (SEQ ID NO;

     102), CCX₈CX₅CX₄CX₃CX₄CCXCX₁C (SEQ ID NO;

     103), CCX₆CCX₅CCCX₄CX₄CX₁₂C (SEQ ID NO;

     104), CX₆CX₂CX₃CCCX₄CX₅CX₃CX₃C (SEQ ID NO;

     105), CX₃CX₅CX₆CX₄CCXCX₅CX₄CXC (SEQ ID NO;

     106), CX₄CX₄CCX₄CX₄CXCX₁₁CX₂CXC (SEQ ID NO;

     107), CX₅CX₂CCX₅CX₄CCX₃CCX₇C (SEQ ID NO;

     108), CX₅CX₅CX₃CX₂CXCCX₄CX₇CXC (SEQ ID NO;

     109), CX₃CX₇CX₃CX₄CCXCX₂CX₅CX₂C (SEQ ID NO;

     110), CX₉CX₃CXCX₄CCX₅CCCX₆C (SEQ ID NO;

     111), CX₉CX₃CXCX₂CXCCX₆CX₃CX₃C (SEQ ID NO;

     112), CX₈CCXCX₃CCX₃CXCX₃CX₄C (SEQ ID NO;

     113), CX₉CCX₄CX₂CXCCXCX₄CX₃C (SEQ ID NO;

     114), CX₁₀CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     115), CX₉CXCX₃CX₂CXCCX₄CX₅CXC (SEQ ID NO;

     116), CX₆CCXCX₅CX₄CCXCX₅CX₂C (SEQ ID NO;

     117), CX₆CCXCX₃CXCCX₃CX₄CC (SEQ ID NO;

     118), CX₆CCXCX₃CXCX₂CXCX₄CX₈C (SEQ ID NO;

     119), CX₄CX₂CCX₃CXCX₄CCX₂CX₃C (SEQ ID NO;

     120), CX₃CX₅CX₃CCCX₄CX₉C (SEQ ID NO;

     121), CCX₉CX₃CXCCX₃CX₅C (SEQ ID NO;

     122), CX₉CX₂CX₃CX₄CCX₄CX₅C (SEQ ID NO;

     123), CX₉CX₇CX₄CCXCX₇CX₃C (SEQ ID NO;

     124), CX₉CX₃CCCX₁₀CX₂CX₃C (SEQ ID NO;

     125), CX₃CX₅CX₅CX₄CCX₁₀CX₆C (SEQ ID NO;

     126), CX₉CX₅CX₄CCXCX₅CX₄C (SEQ ID NO;

     127), CX₇CXCX₆CX₄CCCX₁₀C (SEQ ID NO;

     128), CX₈CX₂CX₄CCX₄CX₃CX₃C (SEQ ID NO;

     129), CX₇CX₅CXCX₄CCX₇CX₄C (SEQ ID NO;

     130), CX₁₁CX₃CX₄CCCX₈CX₂C (SEQ ID NO;

     131), CX₂CX₃CX₄CCX₄CX₅CX₁₅C (SEQ ID NO;

     132), CX₉CX₅CX₄CCX₇C (SEQ ID NO;

     133), CX₉CX₇CX₃CX₂CX₆C (SEQ ID NO;

     134), CX₉CX₅CX₄CCX₁₄C (SEQ ID NO;

     135), CX₉CX₅CX₄CCX₈C (SEQ ID NO;

     136), CX₉CX₆CX₄CCXC (SEQ ID NO;

     137), CX₅CCX₇CX₄CX₁₂ (SEQ ID NO;

     138), CX₁₀CX₃CX₄CCX₄C (SEQ ID NO;

     139), CX₉CX₄CCX₅CX₄C (SEQ ID NO;

     140), CX₁₀CX₃CX₄CX₇CXC (SEQ ID NO;

     141), CX₇CX₇CX₂CX₂CX₃C (SEQ ID NO;

     142), CX₉CX₄CX₄CCX₆C (SEQ ID NO;

     143), CX₇CXCX₃CXCX₆C (SEQ ID NO;

     144), CX₇CXCX₄CXCX₄C (SEQ ID NO;

     145), CX₉CX₅CX₄C (SEQ ID NO;

     146), CX₃CX₆CX₈C (SEQ ID NO;

     147), CX₁₀CXCX₄C (SEQ ID NO;

     148), CX₁₀CCX₄C (SEQ ID NO;

     149), CX₁₅C (SEQ ID NO;

     150), CX₁₀C (SEQ ID NO;

     151), and CX₉C (SEQ ID NO;

     152).

166. The antibody heavy chain variable region of any one of claim 146-165, wherein the ultralong CDR3 comprises 2 to 6 disulfide bonds.

167. The antibody heavy chain variable region of any one of claim 146-165, wherein the ultralong CDR3 comprises a non-antibody sequence.

168. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of GSKHRLRDYFLYNE (SEQ ID NO;

     501), GSKHRLRDYFLYN (SEQ ID NO;

     502), GSKHRLRDYFLY (SEQ ID NO;

     503), GSKHRLRDYFL (SEQ ID NO;

     504), GSKHRLRDYF (SEQ ID NO;

     505), GSKHRLRDY (SEQ ID NO;

     506), or GSKHRLRD (SEQ ID NO;

     507), a non-antibody sequence, and an amino acid sequence of any one of YGPNYEEWGDYLATLDV (SEQ ID NO;

     536), GPNYEEWGDYLATLDV (SEQ ID NO;

     537), PNYEEWGDYLATLDV (SEQ ID NO;

     538), NYEEWGDYLATLDV (SEQ ID NO;

     539), YEEWGDYLATLDV (SEQ ID NO;

     540), or EEWGDYLATLDV (SEQ ID NO;

     541), and

wherein V2 comprises an amino acid sequence of WGQGLLVTVSS (SEQ ID NO;

     500).

169. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of EAGGPDYRNGYNY (SEQ ID NO;

     508), EAGGPDYRNGYN (SEQ ID NO;

     509), EAGGPDYRNGY (SEQ ID NO;

     510), EAGGPDYRNG (SEQ ID NO;

     511), EAGGPDYRN (SEQ ID NO;

     512), EAGGPDYR (SEQ ID NO;

     513), EAGGPDY (SEQ ID NO;

     514), or EAGGPD (SEQ ID NO;

     515), a non-antibody sequence, and an amino acid sequence of any one of YDFYDGYYNYHYMDV (SEQ ID NO;

     542), DFYDGYYNYHYMDV (SEQ ID NO;

     543), FYDGYYNYHYMDV (SEQ ID NO;

     544), YDGYYNYHYMDV (SEQ ID NO;

     545), DGYYNYHYMDV (SEQ ID NO;

     546), GYYNYHYMDV (SEQ ID NO;

     547), or YYNYHYMDV (SEQ ID NO;

     548),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

170. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of EAGGPIWHDDVKY (SEQ ID NO;

     516), EAGGPIWHDDVK (SEQ ID NO;

     517), EAGGPIWHDDV (SEQ ID NO;

     518), EAGGPIWHDD (SEQ ID NO;

     519), EAGGPIWHD (SEQ ID NO;

     520), EAGGPIWH (SEQ ID NO;

     521), EAGGPIW (SEQ ID NO;

     522), or EAGGPI (SEQ ID NO;

     523), a non-antibody sequence, and an amino acid sequence of any one of YDFNDGYYNYHYMDV (SEQ ID NO;

     549), DFYDGYYNYHYMDV (SEQ ID NO;

     550), FYDGYYNYHYMDV (SEQ ID NO;

     551), YDGYYNYHYMDV (SEQ ID NO;

     552), DGYYNYHYMDV (SEQ ID NO;

     553), or GYYNYHYMDV (SEQ ID NO;

     554),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

     500).

171. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of GTDYTIDDQGI (SEQ ID NO;

     524), GTDYTIDDQG (SEQ ID NO;

     525), GTDYTIDDQ (SEQ ID NO;

     526), GTDYTIDD (SEQ ID NO;

     527), GTDYTID (SEQ ID NO;

     528), or GTDYTI (SEQ ID NO;

     529), a non-antibody sequence, and an amino acid sequence of any one of QGIRYQGSGTFWYFDV (SEQ ID NO;

     555), GIRYQGSGTFWYFDV (SEQ ID NO;

     556), IRYQGSGTFWYFDV (SEQ ID NO;

     557), RYQGSGTFWYFDV (SEQ ID NO;

     558), YQGSGTFWYFDV (SEQ ID NO;

     559), QGSGTFWYFDV (SEQ ID NO;

     560), GSGTFWYFDV (SEQ ID NO;

     561), SGTFWYFDV (SEQ ID NO;

     562), or GTFWYFDV (SEQ ID NO;

     563),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

500).

172. The antibody heavy chain variable region of claim 146,

wherein V1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence of any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569), a non-antibody sequence, and an amino acid sequence of any one of YNLGYSYFYYMDG (SEQ ID NO;

     564), NLGYSYFYYMDG (SEQ ID NO;

     565), LGYSYFYYMDG (SEQ ID NO;

     566), GYSYFYYMDG (SEQ ID NO;

     567), YSYFYYMDG (SEQ ID NO;

     568), or SYFYYMDG (SEQ ID NO;

     569),

wherein V2 comprises an amino acid sequence selected of WGQGLLVTVSS (SEQ ID NO;

500).

173. The antibody heavy claim variable region of claim 146,

wherein VI comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

735, SEQ ID NO;

737, SEQ ID NO;

739, SEQ ID NO;

741, SEQ ID NO;

743, SEQ ID NO;

745, SEQ ID NO;

747, and SEQ ID NO;

749,

wherein the ultralong CDR3 comprises an amino acid sequence that is SEQ ID NO;

498 and an amino acid sequence that is SEQ ID NO;

499,

wherein V2 comprises an amino acid sequence that is SEQ ID NO;

500.

174. The antibody heavy chain variable region of claim 167, wherein the non-antibody sequence is a synthetic sequence.

175. The antibody heavy chain variable region of claim 167, wherein the non-antibody sequence is a cytokine sequence, a lymphokine sequence, a chemokine sequence, a growth factor sequence, a hormone sequence, or a toxin sequence.

176. The antibody heavy chain variable region of claim 167, wherein the non-antibody sequence is an IL-8 sequence, an IL-21 sequence, an SDF-1 (alpha) sequence, a somatostatin sequence, a chlorotoxin sequence, a Pro-TxII sequence, a ziconotide sequence, an ADWX-1 sequence, an HsTx1 sequence, an OSK1 sequence, a Pi2 sequence, a Hongotoxin (HgTX) sequence, a Margatoxin sequence, an Agitoxin-2 sequence, a Pi3 sequence, a Kaliotoxin sequence, an Anuroctoxin sequence, a Charybdotoxin sequence, a Tityustoxin -K- alpha sequence, a Maurotoxin sequence, a Ceratotoxin 1 (CcoTx1) sequence, a CcoTx2 sequence, a CcoTx3 sequence, a Phrixotoxin 3 (PaurTx3) sequence, a Hanatoxin 1 sequence, a Phrixotoxin 1 sequence, a Huwentoxin-IV sequence, an α

-conotoxin ImI sequence, an α

-conotoxin EpI sequence, an α

-conotoxin PnIA sequence, an α

-conotoxin PnIB sequence, an α

-conotoxin MII sequence, an α

-conotoxin AuIA sequence, an α

-conotoxin AuIB sequence, an α

-conotoxin AuIC sequence, a conotoxin κ

-PVIIA sequence, a charybdotoxin sequence, a neurotoxin B-IV sequence, a crotamine sequence, a ω

-GVIA (conotoxin) sequence, a κ

-hefutoxin 1 sequence, a Css4 sequence, a Bj-xtrIT sequence, a BcIV sequence, a Hm-1 sequence, a Hm-2 sequence, a GsAF-I (β

-theraphotoxin-Gr1b) sequence, a Protoxin I (ProTx-I sequence, a β

-theraphotoxin-Tp1a) sequence, a Protoxin II (ProTx II) sequence, a Huwentoxin I sequence, a μ

-Conotoxin PIIIA sequence, a Jingzhaotoxin-III (β

-TRTX-Cj1a) sequence, a GsAF-II (Kappa-theraphotoxin-Gr2c) sequence, a ShK (Stichodactyla toxin) sequence, a HsTx1 sequence, a Guangxitoxin 1E (GxTx-1E) sequence, a Maurotoxin sequence, a Charybdotoxin (ChTX) sequence, an Iberiotoxin (IbTx) sequence, a Leiurotoxin 1 (scyllatoxin) sequence, a Tamapin sequence, a Kaliotoxin-1 (KTX) sequence, a Purotoxin1 (PT-1) sequence, or a GpTx-1 sequence, a MOKA Toxin sequence, a OSK1 (P12, K16, D20) sequence, a OSK1 (K16, D20) sequence, a HmK sequence, a ShK (K16, Y26, K29) sequence, a ShK (K16) sequence, a ShK-A (K16) sequence, a ShK (K16, E30) sequence, a ShK (Q21) sequence, a ShK (L21) sequence, a ShK (F21) sequence, a ShK (121) sequence, or a ShK (A21) sequence.

177. The antibody heavy chain variable region of claim 172, wherein the non-antibody sequence is any one of SEQ ID NOS:

475-481, 599-655, 666-698, 727-733, 808-810, and 831-835.

178. The antibody heavy chain variable region of claim 177, wherein the antibody heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:

770-779, 784-791, 903-922 and 925-955.

179. The antibody heavy chain variable region of claim 167, wherein the antibody heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

941.

184. An antibody or binding fragment thereof comprising the antibody heavy chain variable region of any one of claims 146-183.

185. The antibody or binding fragment thereof of claim 184, wherein the heavy chain variable region further comprises a constant heavy chain 1 (CH1) region.

186. The antibody or binding fragment thereof claim 184, wherein the heavy chain variable region further comprises an amino acid sequence of SEQ ID NO:

390.

187. The antibody or binding fragment thereof of claim 184, wherein the antibody or binding fragment further comprises a light chain variable region.

188. The antibody or binding fragment thereof of claim 187, wherein the light chain variable region further comprising a constant light chain (CL) region.

189. An isolated polynucleotide encoding the antibody heavy chain variable region of any one of claims 146-183.

190. A vector comprising the polynucleotide of claim 189.

191. A host cell comprising the vector of claim 190.

194. The antibody heavy chain variable region of claim 146, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵ motif,

wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q).

195. The antibody heavy chain variable region of claim 194, wherein the X¹X²X³X⁴X⁵ motif is TTVHQ (SEQ ID NO:

153), TSVHQ (SEQ ID NO;

     154), SSVTQ (SEQ ID NO;

     155), STVHQ (SEQ ID NO;

     156), ATVRQ (SEQ ID NO;

     157), TTVYQ (SEQ ID NO;

     158), SPVHQ (SEQ ID NO;

     159), ATVYQ (SEQ ID NO;

     160), TAVYQ (SEQ ID NO;

     161), TNVHQ (SEQ ID NO;

     162), ATVHQ (SEQ ID NO;

     163), STVYQ (SEQ ID NO;

     164), TIVHQ (SEQ ID NO;

     165), AIVYQ (SEQ ID NO;

     166), TTVFQ (SEQ ID NO;

     167), AAVFQ (SEQ ID NO;

     168), GTVHQ (SEQ ID NO;

     169), ASVHQ (SEQ ID NO;

     170), TAVFQ (SEQ ID NO;

     171), ATVFQ (SEQ ID NO;

     172), AAAHQ (SEQ ID NO;

     173), VWYQ (SEQ ID NO;

     174), GTVFQ (SEQ ID NO;

     175), TAVHQ (SEQ ID NO;

     176), ITVHQ (SEQ ID NO;

     177), ITAHQ (SEQ ID NO;

     178), VTVHQ (SEQ ID NO;

     179);

AAVHQ (SEQ ID NO;

     180), GTVYQ (SEQ ID NO;

     181), TTVLQ (SEQ ID NO;

     182), TTTHQ (SEQ ID NO;

     183), or TTDYQ (SEQ ID NO;

     184).

196. The antibody heavy chain variable region of claim 146, wherein the ultralong CDR3 comprises a (X^aX^b)_z motif,

wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein z is 1-4.

197. The antibody heavy chain variable region of claim 196, wherein the (X^aX^b)_z motif is CYTYNYEF (SEQ ID NO:

217), HYTYTYDF (SEQ ID NO;

     218), HYTYTYEW (SEQ ID NO;

     219), KHRYTYEW (SEQ ID NO;

     220), NYIYKYSF (SEQ ID NO;

     221), PYIYTYQF (SEQ ID NO;

     222), SFTYTYEW (SEQ ID NO;

     223), SYIYIYQW (SEQ ID NO;

     224), SYNYTYSW (SEQ ID NO;

     225), SYSYSYEY (SEQ ID NO;

     226), SYTYNYDF (SEQ ID NO;

     227), SYTYNYEW (SEQ ID NO;

     228), SYTYNYQF (SEQ ID NO;

     229), SYVWTHNF (SEQ ID NO;

     230), TYKYVYEW (SEQ ID NO;

     231), TYTYTYEF (SEQ ID NO;

     232), TYTYTYEW (SEQ ID NO;

     233), VFTYTYEF (SEQ ID NO;

     234), AYTYEW (SEQ ID NO;

     235), DYIYTY (SEQ ID NO;

     236), IHSYEF (SEQ ID NO;

     237), SFTYEF (SEQ ID NO;

     238), SHSYEF (SEQ ID NO;

     239), THTYEF (SEQ ID NO;

     240), TWTYEF (SEQ ID NO;

     241), TYNYEW (SEQ ID NO;

     242), TYSYEF (SEQ ID NO;

     243), TYSYEH (SEQ ID NO;

     244), TYTYDF (SEQ ID NO;

     245), TYTYEF (SEQ ID NO;

     246), TYTYEW (SEQ ID NO;

     247), AYEF (SEQ ID NO;

     248), AYSF (SEQ ID NO;

     249), AYSY (SEQ ID NO;

     250), CYSF (SEQ ID NO;

     251), DYTY (SEQ ID NO;

     252), KYEH (SEQ ID NO;

     253), KYEW (SEQ ID NO;

     254), MYEF (SEQ ID NO;

     255), NWIY (SEQ ID NO;

     256), NYDY (SEQ ID NO;

     257), NYQW (SEQ ID NO;

     258), NYSF (SEQ ID NO;

     259), PYEW (SEQ ID NO;

     260), RYNW (SEQ ID NO;

     261), RYTY (SEQ ID NO;

     262), SYEF (SEQ ID NO;

     263), SYEH (SEQ ID NO;

     264), SYEW (SEQ ID NO;

     265), SYKW (SEQ ID NO;

     266), SYTY (SEQ ID NO;

     267), TYDF (SEQ ID NO;

     268), TYEF (SEQ ID NO;

     269), TYEW (SEQ ID NO;

     270), TYQW (SEQ ID NO;

     271), TYTY (SEQ ID NO;

     272), or VYEW (SEQ ID NO;

     273).

198. The antibody heavy chain variable region of claim 197, wherein the (X^aX^b)_z motif is YXYXYX.

199. The antibody heavy chain variable region of claim 146, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵X_n motif,

wherein X₁ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X₂ is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X₃ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X₄ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), wherein X₅ is glutamine (Q), and wherein n is 27-54.

200. The antibody heavy chain variable region of claim 146, wherein the ultralong CDR3 comprises X_n(X^aX^b)_z motif,

wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), wherein n is 27-54, and wherein z is 1-4.

201. The antibody heavy chain variable region of claim 146, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵X_n(X^aX^b)_z motif,

wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q), wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), wherein n is 27-54, and wherein z is 1-4.

213. The antibody heavy chain variable region of any one of claims 146 to 149, wherein V1 comprises an amino acid sequence of SEQ ID NO:

739, wherein the ultralong CDR3 comprises an amino acid sequence of SEQ ID NO;

498 and SEQ ID NO;

499, and wherein V2 comprises an amino acid sequence of SEQ ID NO;

500.

192. A nucleic acid library comprising a plurality of polynucleotides comprising nucleic acid sequences encoding for an antibody heavy chain variable region comprising a sequence of the formula V1-X-V2, wherein V1 comprises an amino acid sequence selected from the group consisting of:

(i) QVQLREWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     735),

(ii) QVQLREWGAGLLKPSETLSLTCAVYGGSFSDKYWSWIRQPPGKGLEWIGEIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     737),

(iii) QVQLREWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGSIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     739),

(iv) QVQLREWGAGLLKPSETLSLTCAVYGGSFSDKYWSWIRQPPGKGLEWIGSIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     741),

(v) QVQLREWGAGLLKPSETLSLTCTASGFSLSDKAVGWIRQPPGKGLEWIGEINH SGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     743),

(vi) QVQLREWGAGLLKPSETLSLTCAVYGGLGSIDTGGNTGSFSGYYWSWIRQPP GKGLEWYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     745),

(vii) QVQLREWGAGLLKPSETLSLTCTASGFSLSDKAVGWIRQPPGKGLEWIGSIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     747), and

(viii) QVQLREWGAGLLKPSETLSLTCTASGFSLSDKAVGWIRQPPGKGLEWLGSI DTGGNTGYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     749);

wherein X comprises an ultralong CDR3; and

wherein V2 comprises an amino acid sequence selected from the group consisting of;

(i) WGHGTAVTVSS (SEQ ID NO;

     570),

(ii) WGKGTTVTVSS (SEQ ID NO;

     571),

(iii) WGKGTTVTVSS (SEQ ID NO;

     572),

(iv) WGRGTLVTVSS (SEQ ID NO;

     573),

(v) WGKGTTVTVSS (SEQ ID NO;

     574), and

(vi) WGQGLLVTVSS (SEQ ID NO;

     500).

193. A library of antibodies comprising antibody heavy chain variable regions comprising a sequence of the formula V1-X-V2, wherein V1 comprises an amino acid sequence selected from the group consisting of:

(i) QVQLREWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     735),

(ii) QVQLREWGAGLLKPSETLSLTCAVYGGSFSDKYWSWIRQPPGKGLEWIGEIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     737),

(iii) QVQLREWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGSIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     739),

(iv) QVQLREWGAGLLKPSETLSLTCAVYGGSFSDKYWSWIRQPPGKGLEWIGSIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     741),

(v) QVQLREWGAGLLKPSETLSLTCTASGFSLSDKAVGWIRQPPGKGLEWIGEINH SGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     743),

(vi) QVQLREWGAGLLKPSETLSLTCAVYGGLGSIDTGGNTGSFSGYYWSWIRQPP GKGLEWYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     745),

(vii) QVQLREWGAGLLKPSETLSLTCTASGFSLSDKAVGWIRQPPGKGLEWIGSIN HSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     747), and

(viii) QVQLREWGAGLLKPSETLSLTCTASGFSLSDKAVGWIRQPPGKGLEWLGSI DTGGNTGYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC (SEQ ID NO;

     749);

wherein X comprises an ultralong CDR3; and

wherein V2 comprises an amino acid sequence selected from the group consisting of;

(i) WGHGTAVTVSS (SEQ ID NO;

     570),

(ii) WGKGTTVTVSS (SEQ ID NO;

     571),

(iii) WGKGTTVTVSS (SEQ ID NO;

     572),

(iv) WGRGTLVTVSS (SEQ ID NO;

     573),

(v) WGKGTTVTVSS (SEQ ID NO;

     574), and

(vi) WGQGLLVTVSS (SEQ ID NO;

500).

202. An antibody heavy chain variable region comprising a sequence of the formula V1-X, wherein V1 comprises an amino acid sequence selected from the group consisting of:

(i) SEQ ID NO;

734 or SEQ ID NO;

735,

(ii) SEQ ID NO;

736 or SEQ ID NO;

737,

(iii) SEQ ID NO;

738 or SEQ ID NO;

739,

(iv) SEQ ID NO;

740 or SEQ ID NO;

741,

(v) SEQ ID NO;

742 or SEQ ID NO;

743,

(vi) SEQ ID NO;

744 or SEQ ID NO;

745,

(vii) SEQ ID NO;

746 or SEQ ID NO 747, and

(viii) SEQ ID NO;

748 or SEQ ID NO;

749; and

wherein X comprises an ultralong CDR3.

203. The antibody heavy chain variable region of claim 202, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵ motif,

wherein X¹ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X² is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X³ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X⁴ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), and wherein X⁵ is glutamine (Q).

204. The antibody heavy chain variable region of claim 203, wherein the X¹X²X³X⁴X⁵ motif is TTVHQ (SEQ ID NO:

153), TSVHQ (SEQ ID NO;

     154), SSVTQ (SEQ ID NO;

     155), STVHQ (SEQ ID NO;

     156), ATVRQ (SEQ ID NO;

     157), TTVYQ (SEQ ID NO;

     158), SPVHQ (SEQ ID NO;

     159), ATVYQ (SEQ ID NO;

     160), TAVYQ (SEQ ID NO;

     161), TNVHQ (SEQ ID NO;

     162), ATVHQ (SEQ ID NO;

     163), STVYQ (SEQ ID NO;

     164), TIVHQ (SEQ ID NO;

     165), AIVYQ (SEQ ID NO;

     166), TTVFQ (SEQ ID NO;

     167), AAVFQ (SEQ ID NO;

     168), GTVHQ (SEQ ID NO;

     169), ASVHQ (SEQ ID NO;

     170), TAVFQ (SEQ ID NO;

     171), ATVFQ (SEQ ID NO;

     172), AAAHQ (SEQ ID NO;

     173), VWYQ (SEQ ID NO;

     174), GTVFQ (SEQ ID NO;

     175), TAVHQ (SEQ ID NO;

     176), ITVHQ (SEQ ID NO;

     177), ITAHQ (SEQ ID NO;

     178), VTVHQ (SEQ ID NO;

     179);

AAVHQ (SEQ ID NO;

     180), GTVYQ (SEQ ID NO;

     181), TTVLQ (SEQ ID NO;

     182), TTTHQ (SEQ ID NO;

     183), or TTDYQ (SEQ ID NO;

     184).

205. The antibody heavy chain variable region of claim 202, wherein the ultralong CDR3 comprises a CX¹X²X³X⁴X⁵ motif.

206. The antibody heavy chain variable region of claim 205, wherein the CX¹X²X³X⁴X⁵ motif is CTTVHQ (SEQ ID NO:

185), CTSVHQ (SEQ ID NO;

     186), CSSVTQ (SEQ ID NO;

     187), CSTVHQ (SEQ ID NO;

     188), CATVRQ (SEQ ID NO;

     189), CTTVYQ (SEQ ID NO;

     190), CSPVHQ (SEQ ID NO;

     191), CATVYQ (SEQ ID NO;

     192), CTAVYQ (SEQ ID NO;

     193), CTNVHQ (SEQ ID NO;

     194), CATVHQ (SEQ ID NO;

     195), CSTVYQ (SEQ ID NO;

     196), CTIVHQ (SEQ ID NO;

     197), CAIVYQ (SEQ ID NO;

     198), CTTVFQ (SEQ ID NO;

     199), CAAVFQ (SEQ ID NO;

     200), CGTVHQ (SEQ ID NO;

     201), CASVHQ (SEQ ID NO;

     202), CTAVFQ (SEQ ID NO;

     203), CATVFQ (SEQ ID NO;

     204), CAAAHQ (SEQ ID NO;

     205), CVVVYQ (SEQ ID NO;

     206), CGTVFQ (SEQ ID NO;

     207), CTAVHQ (SEQ ID NO;

     208), CITVHQ (SEQ ID NO;

     209), CITAHQ (SEQ ID NO;

     210), CVTVHQ (SEQ ID NO;

     211);

CAAVHQ (SEQ ID NO;

     212), CGTVYQ (SEQ ID NO;

     213), CTTVLQ (SEQ ID NO;

     214), CTTTHQ (SEQ ID NO;

     215), or CTTDYQ (SEQ ID NO;

     216).

207. The antibody heavy chain variable region of claim 202, wherein the ultralong CDR3 comprises a (X^aX^b)_z motif,

wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein z is 1-4.

208. The antibody heavy chain variable region of claim 207, wherein the (X^aX^b)_z motif is CYTYNYEF (SEQ ID NO:

217), HYTYTYDF (SEQ ID NO;

     218), HYTYTYEW (SEQ ID NO;

     219), KHRYTYEW (SEQ ID NO;

     220), NYIYKYSF (SEQ ID NO;

     221), PYIYTYQF (SEQ ID NO;

     222), SFTYTYEW (SEQ ID NO;

     223), SYIYIYQW (SEQ ID NO;

     224), SYNYTYSW (SEQ ID NO;

     225), SYSYSYEY (SEQ ID NO;

     226), SYTYNYDF (SEQ ID NO;

     227), SYTYNYEW (SEQ ID NO;

     228), SYTYNYQF (SEQ ID NO;

     229), SYVWTHNF (SEQ ID NO;

     230), TYKYVYEW (SEQ ID NO;

     231), TYTYTYEF (SEQ ID NO;

     232), TYTYTYEW (SEQ ID NO;

     233), VFTYTYEF (SEQ ID NO;

     234), AYTYEW (SEQ ID NO;

     235), DYIYTY (SEQ ID NO;

     236), IHSYEF (SEQ ID NO;

     237), SFTYEF (SEQ ID NO;

     238), SHSYEF (SEQ ID NO;

     239), THTYEF (SEQ ID NO;

     240), TWTYEF (SEQ ID NO;

     241), TYNYEW (SEQ ID NO;

     242), TYSYEF (SEQ ID NO;

     243), TYSYEH (SEQ ID NO;

     244), TYTYDF (SEQ ID NO;

     245), TYTYEF (SEQ ID NO;

     246), TYTYEW (SEQ ID NO;

     247), AYEF (SEQ ID NO;

     248), AYSF (SEQ ID NO;

     249), AYSY (SEQ ID NO;

     250), CYSF (SEQ ID NO;

     251), DYTY (SEQ ID NO;

     252), KYEH (SEQ ID NO;

     253), KYEW (SEQ ID NO;

     254), MYEF (SEQ ID NO;

     255), NWIY (SEQ ID NO;

     256), NYDY (SEQ ID NO;

     257), NYQW (SEQ ID NO;

     258), NYSF (SEQ ID NO;

     259), PYEW (SEQ ID NO;

     260), RYNW (SEQ ID NO;

     261), RYTY (SEQ ID NO;

     262), SYEF (SEQ ID NO;

     263), SYEH (SEQ ID NO;

     264), SYEW (SEQ ID NO;

     265), SYKW (SEQ ID NO;

     266), SYTY (SEQ ID NO;

     267), TYDF (SEQ ID NO;

     268), TYEF (SEQ ID NO;

     269), TYEW (SEQ ID NO;

     270), TYQW (SEQ ID NO;

     271), TYTY (SEQ ID NO;

     272), or VYEW (SEQ ID NO;

     273).

209. The antibody heavy chain variable region of claim 207, wherein the (X^aX^b)_z motif is YXYXYX.

210. The antibody heavy chain variable region of claim 202, wherein the ultralong CDR3 comprises a X¹X²X³X⁴X⁵X_n motif,

wherein X₁ is threonine (T), glycine (G), alanine (A), serine (S), or valine (V), wherein X₂ is serine (S), threonine (T), proline (P), isoleucine (I), alanine (A), valine (V), or asparagine (N), wherein X₃ is valine (V), alanine (A), threonine (T), or aspartic acid (D), wherein X₄ is histidine (H), threonine (T), arginine (R), tyrosine (Y), phenylalanine (F), or leucine (L), wherein X₅ is glutamine (Q), and wherein n is 27-54.

211. The antibody heavy chain variable region of claim 202, wherein the ultralong CDR3 comprises X_n(X^aX^b)_z motif,

wherein X^a is any amino acid residue, X^b is an aromatic amino acid selected from the group consisting of:

tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), wherein n is 27-54, and wherein z is 1-4.