COMPOSITIONS AND METHODS FOR SIMULTANEOUS BIVALENT AND MONOVALENT CO-ENGAGEMENT OF ANTIGENS

• US 20110054151A1
• Filed: 09/02/2010
• Published: 03/03/2011
• Est. Priority Date: 09/02/2009
• Status: Active Grant

• Current Assignee: Xencor, Inc.
• Original Assignee: Xencor, Inc.
• Inventors: Lazar, Gregory A., Moore, Gregory L.
• Granted Patent: US 9,493,578 B2
• Time in Patent Office: Days
• US Class Current: 530/389.2
• CPC Class Codes: A61K 47/6835 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/64 comprising a combination of variable region and constant region components
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Immunoglobulin compositions that simultaneously co-engage antigens, where one of the antigens is bound bivalently and the other antigen is bound monovalently. The novel immunoglobulins described preferably utilize heterodimeric Fc regions.

Claims

1. An antibody analog comprising:

a) a first heavy chain and an associated light chain, wherein said first heavy and light chains form a first antigen binding site, wherein the C-terminus of the CH3 domain of said first heavy chain is covalently attached to a C-terminal variable heavy domain;

b) a second heavy chain and an associated light chain, wherein said second heavy and light chains form a second antigen binding site, wherein the C-terminus of the CH3 domain of said second heavy chain is covalently attached to a C-terminal variable light domain;

such that said C-terminal variable heavy and light domains form a third antigen binding site.

2. An antibody analog according to claim 1 wherein two of said antigen binding sites are the same and the third is different.

3. An antibody analog according to claim 1 wherein the antigen bound by said third antigen binding site is CD3.

4. An antibody analog according to claim 1 wherein the antigen bound by said third antigen binding site is Fcγ

RIIb.

5. An antibody analog according to claim 1 wherein all three of said antigen binding sites are the same.

6. An antibody analog according to claim 1 wherein said the C-terminus of said C-terminal variable heavy domain is covalently attached to a CH1 domain and wherein said C-terminus of said C-terminal variable light domain is covalently attached to a CL domain.

7. An antibody analog according to claim 1 wherein each heavy chain comprises at least one amino acid substitution within the Fc region.

8. An antibody analog according to claim 7 wherein each heavy chain comprises a different amino acid substitution, such that a heterodimeric Fc region is more stable than a homodimeric Fc region.

9. An antibody analog according to claim 7 wherein said substitution reduces binding to at least one Fcγ

R receptor.

10. An antibody analog according to claim 7 wherein said amino acid substitution increases binding to at least one Fcγ

R receptor.

11. An antibody analog according to claim 7 wherein said amino acid substitution increases binding to the FcRn receptor.

12. An antibody analog according to claim 7 wherein said amino acid substitutions are selected from the group consisting of 349A, 349C, 349E, 349I, 349K, 349S, 349T, 349W, 351E, 351K, 354C, 356K, 357K, 364C, 364D, 364E, 364F, 364G, 364H, 364R, 364T, 364Y, 366D, 366K, 366S, 366W, 366Y, 368A, 368E, 368K, 368S, 370C, 370D, 370E, 370G, 370R, 370S, 370V, 392D, 392E, 394F, 394S, 394W, 394Y, 395T, 395V, 396T, 397E, 397S, 397T, 399K, 401 K, 405A, 405S, 407T, 407V, 409D, 409E, 411 D, 411 E, 411K, and 439D.

13. An antibody analog comprising:

a) a first heavy chain comprising a variable heavy domain;

b) a second chain comprising the Fc domain of a heavy chain covalently linked to a light chain, wherein said first heavy chain and said second chain form a first antigen binding site;

wherein the C-terminus of the CH3 domain of said first heavy chain is covalently attached to a variable heavy domain and the C-terminus of the CH3 domain of said second chain is covalently attached to a variable light domain, such that said variable heavy and light domains form a second antigen binding site.

14. An antibody analog according to claim 13 wherein a CH1 domain is covalently attached to said variable heavy domain covalently attached to the CH3 domain of said first heavy chain and wherein a CL domain is covalently attached to said variable light domain covalently attached to said CH3 domain of said second chain.

15. An antibody analog according to claim 13, wherein the wherein each of said protein chains comprises a variant CH3 domain relative to a native CH3 domain.

16. An antibody analog according to claim 15, wherein each of said variant CH3 domains comprise different amino acid substitutions, such that a heterodimeric protein pair is more stable than a homodimeric protein pair.

17. An antibody analog according to claim 16, wherein said substitution is selected from the group consisting of 349A, 349C, 349E, 349I, 349K, 349S, 349T, 349W, 351E, 351K, 354C, 356K, 357K, 364C, 364D, 364E, 364F, 364G, 364H, 364R, 364T, 364Y, 366D, 366K, 366S, 366W, 366Y, 368A, 368E, 368K, 368S, 370C, 370D, 370E, 370G, 370R, 370S, 370V, 392D, 392E, 394F, 394S, 394W, 394Y, 395T, 395V, 396T, 397E, 397S, 397T, 399K, 401 K, 405A, 405S, 407T, 407V, 409D, 409E, 411D, 411E, 411K, and 439D, wherein numbering is according to the EU index as in Kabat.