Antibodies specifically binding PD-1, TIM-3 or PD-1 and TIM-3 and their uses

Patent metadata

Field	Value
Publication number	US-10894830-B2
Application number	US-201615340109-A
Country	US
Kind code	B2
Filing date	Nov 1, 2016
Priority date	Nov 3, 2015
Publication date	Jan 19, 2021
Grant date	Jan 19, 2021

Abstract

The present invention relates to antibodies specifically binding PD-1, TIM-3 or PD-1 and TIM-3, polynucleotides encoding the antibodies or fragments, and methods of making and using the foregoing.

First claim

What is claimed:

1. An isolated antagonistic antibody or an antigen-binding portion thereof specifically binding PD-1, comprising a heavy chain complementarity determining region (HCDR) 1 a HCDR2 and a HCDR3 of SEQ ID NOs: 10, 14 and 17, respectively, and a light chain complementarity determining region (LCDR)-1, a LCDR2 and a LCDR3 of SEQ ID NOs: 23, 26 and 32, respectively.

2. The antibody or the antigen-binding portion thereof of claim 1 , comprising a heavy chain variable region (VH) of SEQ ID NO: 48 and a light chain variable region (VL) of SEQ ID NO: 56.

3. The antibody or the antigen-binding portion thereof of claim 1 , wherein the antibody is human or humanized.

4. The antibody or the antigen-binding portion thereof of claim 3 , wherein the antibody is
a) an IgG1 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in an Fc region;
b) an IgG2 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in the Fc region;
c) an IgG3 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in the Fc region;
d) an IgG4 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in the Fc region;
e) an IgG1 isotype comprising L234A, L235A, G237A, P238S, H268A, A330S and P331 S substitutions;
f) an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331 S substitutions;
g) an IgG4 isotype comprising F234A, L235A, G237A, P238S and Q268A substitutions;
h) an IgG1 isotype comprising L234A, L235A or L234A and L235A substitutions;
i) an IgG4 isotype comprising F234A, L235A or F234A and L235A substitutions;
j) an IgG2 isotype comprising a V234A substitution;
k) an IgG4 isotype comprising a S228P substitution; or
l) an IgG4 isotype comprising S228P, F234A and L235A substitutions, wherein residue numbering is according to the EU Index.

5. The antibody or the antigen-binding portion thereof of claim 2 , comprising a heavy chain (HC) of SEQ ID NO: 72 and a light chain (LC) of SEQ ID NO: 73.

6. The antibody or the antigen-binding portion thereof of claim 2 , wherein the antibody is a bispecific antibody, optionally binding PD-Ll (SEQ ID NO: 5), PD-L2 (SEQ ID NO: 8), LAG-3 (SEQ ID NO: 293), TIM-3 (SEQ ID NO: 138), CEACAM-1 (SEQ ID NO: 296), CEACAM-5 (SEQ ID NO: 307), OX-40 (SEQ ID NO: 279), GITR (SEQ ID NO: 271), CD27 (SEQ ID NO: 280), VISTA (SEQ ID NO: 286), CD137 (SEQ ID NO: 281), TIGIT (SEQ ID NO:
301) or CTLA-4 (SEQ ID NO: 292).

7. A pharmaceutical composition comprising the antibody or the antigen-binding portion thereof of claim 2 and a pharmaceutically accepted carrier.

8. An isolated antagonistic antibody specifically binding PD-1 or an antigen-binding portion thereof, comprising
a) the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively;
b) the VH of SEQ ID NO: 64 and the VL of SEQ ID NO: 65; and/or
c) the HC of SEQ ID NO: 74 and the LC of SEQ ID NO: 75.

9. A pharmaceutical composition comprising the antibody or the antigen-binding portion thereof of claim 8 and a pharmaceutically accepted carrier.

10. A kit comprising the antibody of claim 2 .

11. The antibody or the antigen-binding portion thereof of claim 6 , wherein the bispecific antibody comprises a first domain specifically binding PD-1 and a second domain specifically binding TIM-3.

12. The antibody or the antigen-binding portion thereof of claim 11 , wherein
a) the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively or SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively; and
b) the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively; or SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively.

13. The antibody or the antigen-binding portion thereof of claim 12 , wherein the bispecific antibody binds TIM-3 within TIM-3 residues 32-47 (WGKGACPVFECGNVVL) (SEQ ID NO: 261), optionally further binding within TIM-3 residues 50-56 (DERDVNY) (SEQ ID NO: 262).

14. The antibody or the antigen-binding portion thereof of claim 13 , wherein
a. the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively, and the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively;
b. the first domain comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56, and the second domain comprises the VH of SEQ ID NO: 146 and the VL of SEQ ID NO: 156;
c. the antibody comprises a first heavy chain (HCl), a first light chain (LC1), a second heavy chain (HC2) and a second light chain (LC2) of SEQ ID NOs: 186, 188, 191 and 194, respectively;
d. the antibody comprises the HCl, the LC1, the HC2 and the LC2 of SEQ ID NOs: 186, 188, 248 and 194, respectively;
e. the antibody comprises the HCl, the LC1, the HC2 and the LC2 of SEQ ID NOs: 241, 188, 245 and 194, respectively; and/or
f. the antibody comprises the HCl, the LC1, the HC2 and the LC2 of SEQ ID NOs: 243, 188, 246 and 194, respectively.

15. The antibody or the antigen-binding portion thereof of claim 12 , wherein the bispecific antibody binds TIM-3 within TIM-3 residues 90-102 (RIQIPGIMNDEKF) (SEQ ID NO: 263), optionally further binding within TIM-3 residues 50-56 (DERDVNY) (SEQ ID NO: 262).

16. The antibody or the antigen-binding portion thereof of claim 15 , wherein
a. the first domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 10, 14, 17, 23, 26 and 32, respectively, and the second domain comprises the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively;
b. the first domain comprises the VH of SEQ ID NO: 48 and the VL of SEQ ID NO: 56, and the second domain comprises the VH of SEQ ID NO: 172 and the VL of SEQ ID NO: 173;
c. the antibody comprises a HCl, a LC1, a HC2 and a LC2 of SEQ ID NOs: 186, 188, 192 and 195, respectively;
d. the antibody comprises the HCl, the LC1, the HC2 and the LC2 of SEQ ID NOs: 241, 188, 244 and 195, respectively; and/or
e. the antibody comprises the HCl, the LC1, the HC2 and the LC2 of SEQ ID NOs: 243, 188, 247 and 195, respectively.

17. The antibody or the antigen-binding portion thereof of claim 11 , wherein the bispecific antibody is
a. an IgG1 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in an Fc region;
b. an IgG2 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in an Fc region;
c. an IgG3 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in an Fc region;
d. an IgG4 isotype, optionally comprising one, two, three, four, five, six, seven, eight, nine or ten substitutions in an Fc region;
e. an IgG1 isotype comprising L234A, L235A, G237A, P238S, H268A, A330S and P331 S substitutions;
f. an IgG2 isotype comprising V234A, G237A, P238S, H268A, V309L, A330S and P331 S substitutions;
g. an IgG4 isotype comprising F234A, L235A, G237A, P238S and Q268A substitutions;
h. an IgG1 isotype comprising L234A, L235A or L234A and L235A substitutions;
i. an IgG4 isotype comprising F234A, L235A or F234A and

Assignees

• Janssen Biotech Inc

Inventors

• Verona Raluca
• Powers Gordon
• Sabins Nina Chi
• Deangelis Nikki A
• Santulli-Marotto Sandra
• Wiehagen Karla R
• Wu Sheng-Jiun
• Ferrante Catherine
• Ubani Enrique Zudaire

Classifications

• C07K16/1145

  Env proteins, e.g. gp41, gp110/120, gp160, V3, principal neutralising domain [PND] or CD4-binding site · CPC title

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K16/2818 Primary

  against CD28 or CD152 · CPC title