Antibodies with low immunogenicity and uses thereof

Patent metadata

Field	Value
Publication number	US-11427632-B2
Application number	US-201716315141-A
Country	US
Kind code	B2
Filing date	Jul 5, 2017
Priority date	Jul 6, 2016
Publication date	Aug 30, 2022
Grant date	Aug 30, 2022

Abstract

Provided herein are antibodies and antigen-binding fragments thereof with low or no immunogenicity in humans and optionally with desirable manufacturing properties. Also provided are compositions comprising such antibodies or antigen-binding fragments, methods of using such antibodies, and methods for making such antibodies.

First claim

What is claimed:

1. An antibody or an antigen-binding fragment thereof, comprising a VH that comprises four VH framework regions (VH FR1-4) and three VH complementarity determining regions (VH CDR1-3) in the following N-terminal to C-terminal order: VH FR1-VH CDR1-VH FR2-VH CDR2-VH FR3-VH CDR3-VH FR4, wherein VH FR1, VH FR2, VH FR3 and VH FR4 comprise the amino acid sequence of:
X H1 QX H3 QLVQSGAEVKKX H5 GX H6 SVKVSCKAS (SEQ ID NO: 5),
WVRQAPGX H12 X H13 LEWMG (SEQ ID NO: 6),
YAQKX H16 QX H17 RVTX H18 TX H19 DX H21 SX H22 STAYMELX H25 SLRX H31 X H27 DTAX H28 YYC (SEQ ID NO: 7), and
WGX H29 GTX H30 VTVSS (SEQ ID NO: 4) respectively,
wherein X H1 is M or no amino acid, X H3 is M, X H5 is P, X H6 is S, X H12 is K, X H13 is G, X H16 is F, X H17 is G, X H18 is I, X H19 is R, X H21 is R, X H22 is T, X H25 is R, X H31 is A, X H27 is E, X H28 is V, X H29 is Q, and X H30 is L.

2. The antibody or antigen-binding fragment of claim 1 , further comprising a light chain variable region (VL) that comprises four VL framework regions (VL FR1-4) and three VL complementarity determining regions (VL CDR1-3) in the following N-terminal to C-terminal order: VL FR1-VL CDR1-VL FR2-VL CDR2-VL FR3-VL CDR3-VL FR4, wherein VL FR1, VL FR2, VL FR3 and VL FR4 comprise the amino acid sequence of:
NIQMTQSPSX L1 X L2 SASVGDRVTITC (SEQ ID NO: 8);
WX L3 QQKPGKX L4 PKHLIY (SEQ ID NO: 9);
GVPSRFSGSGSGTEFTLTISSLQPEDFATYYC (SEQ ID NO: 10); and
FGGGTKVEIK (SEQ ID NO: 11), respectively,
wherein X L1 is S, X L2 is L, X L3 is F, and X L4 is V.

3. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment specifically binds to CD47 and comprises:
(i) a VH that comprises four VH framework regions (VH FR1-4) and three VH complementarity determining regions (VH CDR1-3) in the following N-terminal to C-terminal order: VH FR1-VH CDR1-VH FR2-VH CDR2-VH FR3-VH CDR3-VH FR4, wherein VH CDR1 comprises the amino acid sequence of GFNIKDYYLH (SEQ ID NO: 59); VH CDR2 comprises the amino acid sequence of WIDPDQGDTE (SEQ ID NO: 60); and VH CDR3 comprises the amino acid sequence of NAAYGSSSYPMDY (SEQ ID NO: 61); and
(ii) a VL that comprises four VL framework regions (VL FR1-4) and three VL complementarity determining regions (VL CDR1-3) in the following N-terminal to C-terminal order: VL FR1-VL CDR1-VL FR2-VL CDR2-VL FR3-VL CDR3-VL FR4, wherein: (A) VL CDR1 comprises the amino acid sequence of X C1 ASQDIHRYLS (SEQ ID NO: 62), wherein X C1 is K or R; VL CDR2 comprises the amino acid sequence of RANRLVS (SEQ ID NO: 63); and VL CDR3 comprises the amino acid sequence of LQYDEFPYT (SEQ ID NO: 64); or (B) VL CDR1 comprises the amino acid sequence of X C1 ASQDIHRYLS (SEQ ID NO: 62), wherein X C1 is K or R; VL CDR2 comprises the amino acid sequence of RX C2 X C3 RFVD (SEQ ID NO: 65), wherein X C2 is any amino acid with a polar or charged side chain, and X C3 is V, I, E, or S; and VL CDR3 comprises the amino acid sequence of LQYDEFPYT (SEQ ID NO: 64).

4. The antibody or antigen-binding fragment of claim 3 , wherein X C2 is Y, E, or H.

5. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises a heavy chain constant region that is a human constant region.

6. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises a light chain constant region selected from the group consisting of a human kappa constant region and a human lambda constant region.

7. The antibody or antigen-binding fragment of claim 1 , wherein the antibody is a monoclonal antibody or antigen-binding fragment thereof.

8. The antibody or antigen-binding fragment of claim 1 , which is conjugated to an agent.

9. A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of claim 1 , and a pharmaceutically acceptable carrier.

10. A polynucleotide comprising a nucleotide sequence encoding the antibody or antigen-binding fragment of claim 1 .

11. A vector comprising the polynucleotide of claim 10 .

12. An isolated cell comprising the polynucleotide of claim 10 .

13. A method of making an antibody or antigen-binding fragment thereof, comprising (a) culturing an isolated cell comprising the polynucleotide of claim 10 ; and (b) isolating the antibody or antigen-binding fragment thereof.

14. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject the antibody or antigen-binding fragment of claim 3 .

15. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of claim 3 , and a pharmaceutically acceptable carrier.

Assignees

• Celgene Corp

Inventors

• Johnson Jeffrey C
• Dearth Lawrence
• Hadjivassiliou Haralambos
• Sun Jeonghoon
• Hariharan Kandasamy

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07K2317/52

  Constant or Fc region; Isotype · CPC title

• C07K16/465

  with additional modified FR-residues · CPC title

• C07K16/461

  Igs containing Ig-regions, -domains or -residues form different species · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title