ANTIBODIES WITH ULTRALONG COMPLEMENTARITY DETERMINING REGIONS

• US 20160168231A1
• Filed: 07/18/2014
• Published: 06/16/2016
• Est. Priority Date: 07/18/2013
• Status: Abandoned Application

• Current Assignee: Taurus Biosciences LLC (Ligand Pharmaceuticals, Inc.)
• Original Assignee: Fabrus, LLC. (Eloxx Pharmaceuticals, Inc.)
• Inventors: DE LOS RIOS, Miguel, BAZIRGAN, Omar
• Application Number:
  US14/905,769
• Publication Number:
  US 20160168231A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C07K 14/43595 from coelenteratae, e.g. medusae
• 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 16/1045 Lentiviridae, e.g. HIV, FIV, SIV
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/522 CH1 domain
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• 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 2319/55 containing a fusion with a toxin, e.g. diphteria toxin

Abstract

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

Claims

1. 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:

2. The antibody heavy chain variable region of claim 1, wherein the ultralong CDR3 comprises an amino acid sequence of:

3. The antibody heavy chain variable region of claim 1, wherein the ultralong CDR3 comprises an amino acid sequence of:

4. The antibody heavy chain variable region of claim 1, wherein the ultralong CDR3 comprises an amino acid sequence of:

5. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of QVQLVQSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQAT GQGLEWMGWMSHEGDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIY YCLT (SEQ ID NO:

496),

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 WGHGTAVTVSS (SEQ ID NO;

     570).

6. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of QRLVESGGGWQPGSSLRLSCAASGFDFSRQGMHWVRQAPG QGLEWVAFIKYDGSEKYHADSVWGRLSISRDNSKDTLYLQMNSLRVEDTATYFCV R (SEQ ID NO:

497),

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 WGKGTTVTVSS (SEQ ID NO;

     571).

7. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of QEQLVESGGGVVQPGGSLRLSCLASGFTFHKYGMHWVRQAP GKGLEWVALISDDGMRKYHSDSMWGRVTISRDNSKNTLYLQFSSLKVEDTAMFF CAR (SEQ ID NO:

498),

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 WGKGTTVTVSS (SEQ ID NO;

     572).

8. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of EVQLVESGGGLIRPGGSLRLSCKGSGFIFENFGFGWVRQGPGK GLEWVSGTNWNGGDSRYGDSVKGRFTISRDNSNNFVYLQMNSLRPEDTAIYYCA R (SEQ ID NO:

499),

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 WGRGTLVTVSS (SEQ ID NO;

     573).

9. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of EVQLVESGGNVVQPGGSLRLSCTASGFSFDDSTMHWVRQAP GKGLQWVSLISWNGGRTYYADSVKGRFTISRDNSKNSLYLQMNSLKTEDTAFYFC AK (SEQ ID NO:

500),

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 WGKGTTVTVSS (SEQ ID NO;

     574).

10. The antibody heavy chain variable region of claim 1, wherein the ultralong CDR3 comprises an amino acid sequence selected from the group consisting of:

11. The antibody heavy chain variable region of any one of claims 1-10, 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.

12. The antibody heavy chain variable region of claim 6, wherein the ultralong CDR3 is 35 amino acids in length or longer.

13. The antibody heavy chain variable region of claim 1-12, wherein the ultralong CDR3 comprises a cysteine motif.

14. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of QVQLVQSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQAT GQGLEWMGWMSHEGDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIY YCLT (SEQ ID NO:

496),

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 WGHGTAVTVSS (SEQ ID NO;

     570).

15. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of QRLVESGGGWQPGSSLRLSCAASGFDFSRQGMHWVRQAPG QGLEWVAFIKYDGSEKYHADSVWGRLSISRDNSKDTLYLQMNSLRVEDTATYFCV R (SEQ ID NO:

497),

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 WGKGTTVTVSS (SEQ ID NO;

     571).

16. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of QEQLVESGGGVVQPGGSLRLSCLASGFTFHKYGMHWVRQAP GKGLEWVALISDDGMRKYHSDSMWGRVTISRDNSKNTLYLQFSSLKVEDTAMFF CAR (SEQ ID NO:

498),

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 WGKGTTVTVSS (SEQ ID NO;

     572).

17. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of EVQLVESGGGLIRPGGSLRLSCKGSGFIFENFGFGWVRQGPGK GLEWVSGTNWNGGDSRYGDSVKGRFTISRDNSNNFVYLQMNSLRPEDTAIYYCA R (SEQ ID NO:

499),

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 WGRGTLVTVSS (SEQ ID NO;

     573).

18. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of EVQLVESGGNVVQPGGSLRLSCTASGFSFDDSTMHWVRQAP GKGLQWVSLISWNGGRTYYADSVKGRFTISRDNSKNSLYLQMNSLKTEDTAFYFC AK (SEQ ID NO:

500),

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 WGKGTTVTVSS (SEQ ID NO;

     574).

19. The antibody heavy chain variable region of any one of claim 13-18, wherein the cysteine motif is selected from the group consisting of:

20. The antibody heavy chain variable region of any one of claim 13-18, wherein the cysteine motif is selected from the group consisting of:

21. The antibody heavy chain variable region of any one of claim 1-20, wherein the ultralong CDR3 comprises 2 to 6 disulfide bonds.

22. The antibody heavy chain variable region of any one of claim 1-20, wherein the ultralong CDR3 comprises a non-antibody sequence.

23. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of QVQLVQSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQAT GQGLEWMGWMSHEGDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIY YCLT (SEQ ID NO:

496),

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 WGHGTAVTVSS (SEQ ID NO;

     570).

24. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of QRLVESGGGWQPGSSLRLSCAASGFDFSRQGMHWVRQAPG QGLEWVAFIKYDGSEKYHADSVWGRLSISRDNSKDTLYLQMNSLRVEDTATYFCV R (SEQ ID NO:

497),

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 WGKGTTVTVSS (SEQ ID NO;

     571).

25. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of QEQLVESGGGVVQPGGSLRLSCLASGFTFHKYGMHWVRQAP GKGLEWVALISDDGMRKYHSDSMWGRVTISRDNSKNTLYLQFSSLKVEDTAMFF CAR (SEQ ID NO:

498),

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 WGKGTTVTVSS (SEQ ID NO;

     572).

26. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of EVQLVESGGGLIRPGGSLRLSCKGSGFIFENFGFGWVRQGPGK GLEWVSGTNWNGGDSRYGDSVKGRFTISRDNSNNFVYLQMNSLRPEDTAIYYCA R (SEQ ID NO:

499),

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 WGRGTLVTVSS (SEQ ID NO;

     573).

27. The antibody heavy chain variable region of claim 1,

wherein V1 comprises an amino acid sequence of EVQLVESGGNVVQPGGSLRLSCTASGFSFDDSTMHWVRQAP GKGLQWVSLISWNGGRTYYADSVKGRFTISRDNSKNSLYLQMNSLKTEDTAFYFC AK (SEQ ID NO:

500),

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 WGKGTTVTVSS (SEQ ID NO;

     574).

28. The antibody heavy chain variable region of claim 22, wherein the non-antibody sequence is a synthetic sequence.

29. The antibody heavy chain variable region of claim 22, 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.

30. The antibody heavy chain variable region of claim 22, 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 Iml sequence, an α

-conotoxin Epl sequence, an α

-conotoxin PnlA sequence, an α

-conotoxin PnlB sequence, an α

-conotoxin MII sequence, an α

-conotoxin AulA sequence, an α

-conotoxin AulB sequence, an α

-conotoxin AulC 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-xtrlT sequence, a BclV 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-Cj1α

) 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 (I21) sequence, or a ShK (A21) sequence.

31. The antibody heavy chain variable region of claim 1 comprising the amino acid sequence of QVQLVQSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQATGQGLEWMGWM SHEGDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIYYCLTGSKHRLRD YFLYNEYGPNYEEWGDYLATLDVWGHGTAVTVSS (SEQ ID NO:

656),

wherein the heavy chain variable region further comprises a non-antibody sequence inserted between any one of;

(i) the L at position 109 and the Y at position 110;

(ii) the Y at position 110 and the N at position 111;

(iii) the N at position 111 and the E at position 112;

(iv) the E at position 112 and the Y at position 113;

(v) the Y at position 113 and the G at position 114;

(vi) the G at position 114 and the P at position 115;

(vii) the P at position 115 and the N at position 116;

or

(viii) the N at position 116 and the Y at position 117, or

wherein the amino acid sequence of YNEYGPN at positions 110 to 116 has been removed and replaced with a non-antibody sequence, or

wherein the P at position 115 has been removed and replaced with a non-antibody sequence.

32. The antibody heavy chain variable region of claim 1 comprising the amino acid sequence of QRLVESGGGWQPGSSLRLSCAASGFDFSRQGMHWVRQAPGQGLEWVAFIKYD GSEKYHADSVWGRLSISRDNSKDTLYLQMNSLRVEDTATYFCVREAGGPDYRNG YNYYDFYDGYYNYHYMDVWGKGTTVTVSS (SEQ ID NO:

657),

wherein the heavy chain variable region further comprises a non-antibody sequence inserted between any one of;

(i) the Y at position 104 and the R at position 105;

(ii) the R at position 105 and the N at position 106;

(iii) the N at position 106 and the G at position 107;

(iv) the G at position 107 and the Y at position 108;

(v) the Y at position 108 and the N at position 109;

(vi) the N at position 109 and the Y at position 110;

(vii) the Y at position 110 and the Y at position 111;

(viii) the Y at position 111 and the D at position 112;

(ix) the D at position 112 and the F at position 113

(x) the F at position 113 and the Y at position 114;

(xi) the Y at position 114 and the D at position 115;

(xi) the D at position 115 and the G at position 116, or

wherein the amino acid sequence of NYYD at positions 109 to 112 has been removed and replaced with a non-antibody sequence, or

wherein the Y at position 110 has been removed and replaced with a non-antibody sequence.

33. The antibody heavy chain variable region of claim 1 comprising the amino acid sequence of QEQLVESGGGWQPGGSLRLSCLASGFTFHKYGMHWVRQAPGKGLEWVALISD DGMRKYHSDSMWGRVTISRDNSKNTLYLQFSSLKVEDTAMFFCAREAGGPIWHD DVKYYDFNDGYYNYHYMDVWGKGTTVTVSS (SEQ ID NO:

658),

wherein the heavy chain variable region further comprises a non-antibody sequence inserted between any on one of;

(i) the W at position 105 and the H at position 106;

(ii) the H at position 106 and the D at position 107;

(iii) the D at position 107 and the D at position 108;

(iv) the D at position 108 and the V at position 109;

or

(v) the V at position 109 and the K at position 110, or

wherein the amino acid sequence of DD at positions 107 to 108 has been removed and replaced with a non-antibody sequence.

34. The antibody heavy chain variable region of claim 1 comprising the amino acid sequence of EVQLVESGGGLIRPGGSLRLSCKGSGFIFENFGFGWVRQGPGKGLEWVSGTNW NGGDSRYGDSVKGRFTISRDNSNNFVYLQMNSLRPEDTAIYYCARGTDYTIDDQG IRYQGSGTFWYFDVWGRGTLVTVSS (SEQ ID NO:

659),

wherein the heavy chain variable region further comprises a non-antibody sequence inserted between any on one of;

(i) the I at position 104 and the D at position 105;

(ii) the D at position 105 and the D at position 106;

(iii) the D at position 106 and the Q at position 107;

(iv) the Q at position 107 and the G at position 108;

or

(v) the G at position 108 and the I at position 109, or

wherein the amino acid sequence of DQ at positions 107 to 108 has been removed and replaced with a non-antibody sequence.

35. The antibody heavy chain variable region of claim 1 comprising the amino acid sequence of EVQLVESGGNVVQPGGSLRLSCTASGFSFDDSTMHWVRQAPGKGLQWVSLISW NGGRTYYADSVKGRFTISRDNSKNSLYLQMNSLKTEDTAFYFCAKDKGDSDYDY NLGYSYFYYMDGWGKGTTVTVSS (SEQ ID NO:

660),

wherein the heavy chain variable region further comprises a non-antibody sequence inserted between any on one of;

(i) the Y at position 105 and the D at position 106;

(ii) the D at position 106 and the Y at position 107;

(iii) the Y at position 107 and the N at position 108;

(iv) the N at position 108 and the L at position 109;

(v) the L at position 109 and the G at position 110;

or

(vi) the G at position 110 and the Y at position 111, or

wherein the amino acid sequence of YNL at positions 107 to 109 has been removed and replaced with a non-antibody sequence.

36. The antibody heavy chain variable region of any one of claims 1-35, wherein the ultralong CDR3 comprises a linker sequence.

37. The antibody heavy chain variable region of claim 36, wherein the linker is linked to a N-terminus, a C-terminus, or both N-terminus and C-terminus of the non-antibody sequence.

38. The antibody heavy chain variable region of claim 36 or 37, 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 756-773, or any combination thereof.

39. The antibody heavy chain variable region of claim 37, wherein the linkers linked to both N-terminus and C-terminus have the same or different amino acid sequence.

40. An antibody or binding fragment thereof comprising the antibody heavy chain variable region of any one of claims 1-39.

41. The antibody or binding fragment thereof of claim 40, wherein the heavy chain variable region further comprises a constant heavy chain 1 (CH1) region.

42. The antibody or binding fragment thereof claim 39, wherein the CH1 region comprises an amino acid sequence selected from SEQ ID NO:

661 to 665.

43. The antibody or binding fragment thereof claim 40, wherein the heavy chain variable region further comprises an amino acid sequence of SEQ ID NO:

390.

44. The antibody or binding fragment thereof of claim 40, wherein the antibody or binding fragment further comprises a light chain variable region.

45. The antibody or binding fragment thereof of claim 44, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO:

734 to 738.

46. The antibody or binding fragment thereof of claim 45, wherein the light chain variable region further comprising a constant light chain (CL) region.

47. The antibody or binding fragment thereof of claim 45, wherein the CL region comprises an amino acid sequence selected from SEQ ID NO:

739 to 743.

48. An isolated polynucleotide encoding the antibody heavy chain variable region of any one of claims 1-39.

49. A vector comprising the polynucleotide of claim 48.

50. A host cell comprising the vector of claim 49.

53. The antibody heavy chain variable region 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).

54. The antibody heavy chain variable region of claim 53, 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), VVVYQ (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).

55. The antibody heavy chain variable region 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.

56. The antibody heavy chain variable region of claim 55, 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).

57. The antibody heavy chain variable region of claim 56, wherein the (X^aX^b)_z motif is YXYXYX.

58. The antibody heavy chain variable region 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.

59. The antibody heavy chain variable region 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.

60. The antibody heavy chain variable region 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.

51. 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:

52. 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:

61. 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:

62. The antibody heavy chain variable region of claim 61, 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).

63. The antibody heavy chain variable region of claim 62, 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), VVVYQ (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).

64. The antibody heavy chain variable region of claim 61, wherein the ultralong CDR3 comprises a CX¹X²X³X⁴X⁵ motif.

65. The antibody heavy chain variable region of claim 64, 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).

66. The antibody heavy chain variable region of claim 61, 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.

67. The antibody heavy chain variable region of claim 66, 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).

68. The antibody heavy chain variable region of claim 66, wherein the (X^aX^b)_z motif is YXYXYX.

69. The antibody heavy chain variable region of claim 61, 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.

70. The antibody heavy chain variable region of claim 61, 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.

71. The antibody heavy chain variable region of claim 61, 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.