IP Library › Granted Patent US 12,060,425

Granted Patent B2

US 12,060,425 · App. 17/051,834 · Granted Aug 13, 2024

High affinity antibodies to PD-1 and LAG-3 and bispecific binding proteins made therefrom

Inventors: Xuan Wu (Shanghai, CN); Shiyong Gong (Shanghai, CN); Chengbin Wu (Shanghai, CN)

Assignee: SHANGHAI EPIMAB BIOTHERAPEUTICS CO., LTD.

C07K16/2818 A61K2039/505 C07K2317/31 C07K2317/515 C07K2317/522 C07K2317/565

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Quick Facts

Patent No.: US 12,060,425
App. No.: 17/051,834
Granted: Aug 13, 2024
Kind: B2

External Links

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Abstract

High-affinity antibodies recognizing Programmed Death Ligand-1 (PD-1) and Lymphocyte Activation Gene 3 protein (LAG-3) are disclosed. Binding sites from humanized anti-PD-1 and anti-LAG-3 antibodies are incorporated into a Fabs-in-Tandem Immunoglobulin format without significant loss of binding affinity, and the resultant bispecific, multivalent binding proteins are able to bind to both PD-1 and LAG-3 simultaneously. Such bispecific FIT-Ig binding proteins are useful for treatment of cancer.

Claims (362)

1. An anti-PD-1 antibody, or an antigen-binding portion thereof, capable of binding human PD-1, wherein the antibody or antigen-binding portion thereof comprises a set of six complementarity determining regions (CDRs), CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, selected from the group consisting of:

CDR

CDR Amino

Set No.

CDR

Acid Sequence

SEQ ID NO

CDR-H1

SYMMS

residues 31-35

of SEQ ID NO: 4

CDR-H2

SMSGGGRDTYYPDSVKG

residues 50-66

of SEQ ID NO: 4

CDR-H3

RGTYAMDY

residues 99-106

of SEQ ID NO: 4

CDR-L1

LASQTIGTWLT

residues 24-34

of SEQ ID NO: 5

CDR-L2

AATSLAD

residues 50-56

of SEQ ID NO: 5

CDR-L3

QQLYSTPWT

residues 89-97

of SEQ ID NO: 5

CDR-H1

TGYYWN

residues 31-36

of SEQ ID NO: 6

CDR-H2

YMSYDGNNNYNPSLKN

residues 51-66

of SEQ ID NO: 6

CDR-H3

DRGTTILGGTMDY

residues 99-111

of SEQ ID NO: 6

CDR-L1

KASQSVSNDVA

residues 24-34

of SEQ ID NO: 7

CDR-L2

YAFYRYT

residues 50-56

of SEQ ID NO: 7

CDR-L3

QQDYSSPWT

residues 89-97

of SEQ ID NO: 7

CDR-H1

FYTMS

residues 31-35

of SEQ ID NO: 8

CDR-H2

TISGGGRDTYYPDSVKG

residues 50-66

of SEQ ID NO: 8

CDR-H3

QGGNYLFAY

residues 99-107

of SEQ ID NO: 8

CDR-L1

KASQDVNTVVA

residues 24-34

of SEQ ID NO: 9

CDR-L2

WASTRHT

residues 50-56

of SEQ ID NO: 9

CDR-L3

QQHYTTPYT

residues 89-97

of SEQ ID NO: 9

CDR-H1

DYGMH

residues 31-35

of SEQ ID NO: 10

CDR-H2

YISSGSYTIYYADTVKG

residues 50-66

of SEQ ID NO: 10

CDR-H3

RGGSSHVNVMDY

residues 99-110

of SEQ ID NO: 10

CDR-L1

KASDHINNWLA

residues 24-34

of SEQ ID NO: 11

CDR-L2

GATSLET

residues 50-56

of SEQ ID NO: 11

CDR-L3

QQYWSPPYT

residues 89-97

of SEQ ID NO: 11

CDR-H1

DNNVE

residues 31-35

of SEQ ID NO: 12

CDR-H2

DINPNNGDTLYSQYFKD

residues 50-66

of SEQ ID NO: 12

CDR-H3

GKSDQFDY

residues 99-106

of SEQ ID NO: 12

CDR-L1

LASQTIGTWLA

residues 24-34

of SEQ ID NO: 13

CDR-L2

AATSLAD

residues 50-56

of SEQ ID NO: 13

CDR-L3

QQLYSSPWT

residues 89-97

of SEQ ID NO: 13

CDR-H1

SYAMS

residues 31-35

of SEQ ID NO: 14

CDR-H2

TISGGGRDTYYPDSVKG

residues 50-66

of SEQ ID NO: 14

CDR-H3

QGGTYLFAS

residues 99-107

of SEQ ID NO: 14

CDR-L1

KASQDVNTAVA

residues 24-34

of SEQ ID NO: 15

CDR-L2

WASTRHT

residues 50-56

of SEQ ID NO: 15

CDR-L3

QQHYTTPYT

residues 89-97

of SEQ ID NO: 15

CDR-H1

DYEMH

residues 31-35

of SEQ ID NO: 16

CDR-H2

VIEPESGGTVYNQKFKG

residues 51-66

of SEQ ID NO: 16

CDR-H3

EGFNSDHYFDY

residues 99-109

of SEQ ID NO: 16

CDR-L1

RSSQNIVHSNGNTYLE

residues 24-39

of SEQ ID NO: 17

CDR-L2

KVFNRFS

residues 55-61

of SEQ ID NO: 17

CDR-L3

FQGSHVPYT

residues 94-102

of SEQ ID NO: 17

CDR-H1

SHLMS

residues 31-35

of SEQ ID NO: 18

CDR-H2

AISGGGADTYYPDSVKG

residues 50-66

of SEQ ID NO: 18

CDR-H3

QILAFDS

residues 99-105

of SEQ ID NO: 18

CDR-L1

HASQNIYVWLN

residues 24-34

of SEQ ID NO: 19

CDR-L2

KASNLHT

residues 50-56

of SEQ ID NO: 19

CDR-L3

QQGQSYPWT

residues 89-97

of SEQ ID NO: 19

CDR-H1

SHLMS

residues 31-35

of SEQ ID NO: 53

CDR-H2

AISGGGADTYYPASVKG

residues 50-66

of SEQ ID NO: 53

CDR-H3

QILAFDA

residues 99-105

of SEQ ID NO: 53

CDR-L1

HASQNIYVWLN

residues 24-34

of SEQ ID NO: 19

CDR-L2

KASNLHT

residues 50-56

of SEQ ID NO: 19

CDR-L3

QQGQSYPWT

residues 89-97

of SEQ ID NO: 19

2. An anti-PD-1 antibody comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH and VL comprise amino acid sequences selected from the group consisting of:

SEQ ID NO: 4 and SEQ ID NO: 5

SEQ ID NO: 8 and SEQ ID NO: 9

SEQ ID NO: 12 and SEQ ID NO: 13

SEQ ID NO: 16 and SEQ ID NO: 17

SEQ ID NO: 20 and SEQ ID NO: 23

SEQ ID NO: 22 and SEQ ID NO: 23

SEQ ID NO: 21 and SEQ ID NO: 24

SEQ ID NO: 20 and SEQ ID NO: 25

SEQ ID NO: 22 and SEQ ID NO: 25

SEQ ID NO: 21 and SEQ ID NO: 26

SEQ ID NO: 20 and SEQ ID NO: 27

SEQ ID NO: 22 and SEQ ID NO: 27

SEQ ID NO: 31 and SEQ ID NO: 34

SEQ ID NO: 33 and SEQ ID NO: 34

SEQ ID NO: 31 and SEQ ID NO: 35

SEQ ID NO: 33 and SEQ ID NO: 35

SEQ ID NO: 31 and SEQ ID NO: 36

SEQ ID NO: 33 and SEQ ID NO: 36

SEQ ID NO: 31 and SEQ ID NO: 37

SEQ ID NO: 33 and SEQ ID NO: 37

SEQ ID NO: 39 and SEQ ID NO: 43

SEQ ID NO: 41 and SEQ ID NO: 43

SEQ ID NO: 38 and SEQ ID NO: 44

SEQ ID NO: 40 and SEQ ID NO: 44

SEQ ID NO: 42 and SEQ ID NO: 44

SEQ ID NO: 39 and SEQ ID NO: 45

SEQ ID NO: 41 and SEQ ID NO: 45

SEQ ID NO: 38 and SEQ ID NO: 46

SEQ ID NO: 40 and SEQ ID NO: 46

SEQ ID NO: 42 and SEQ ID NO: 46

SEQ ID NO: 39 and SEQ ID NO: 47

SEQ ID NO: 41 and SEQ ID NO: 47

SEQ ID NO: 48 and SEQ ID NO: 55

SEQ ID NO: 50 and SEQ ID NO: 55

SEQ ID NO: 52 and SEQ ID NO: 55

SEQ ID NO: 54 and SEQ ID NO: 55

SEQ ID NO: 49 and SEQ ID NO: 56

SEQ ID NO: 51 and SEQ ID NO: 56

SEQ ID NO: 53 and SEQ ID NO: 56

SEQ ID NO: 48 and SEQ ID NO: 57

SEQ ID NO: 50 and SEQ ID NO: 57

SEQ ID NO: 52 and SEQ ID NO: 57

SEQ ID NO: 54 and SEQ ID NO: 57

SEQ ID NO: 6 and SEQ ID NO: 7

SEQ ID NO: 10 and SEQ ID NO: 11

SEQ ID NO: 14 and SEQ ID NO: 15

SEQ ID NO: 18 and SEQ ID NO: 19

SEQ ID NO: 21 and SEQ ID NO: 23

SEQ ID NO: 20 and SEQ ID NO: 24

SEQ ID NO: 22 and SEQ ID NO: 24

SEQ ID NO: 21 and SEQ ID NO: 25

SEQ ID NO: 20 and SEQ ID NO: 26

SEQ ID NO: 22 and SEQ ID NO: 26

SEQ ID NO: 21 and SEQ ID NO: 27

SEQ ID NO: 30 and SEQ ID NO: 34

SEQ ID NO: 32 and SEQ ID NO: 34

SEQ ID NO: 30 and SEQ ID NO: 35

SEQ ID NO: 32 and SEQ ID NO: 35

SEQ ID NO: 30 and SEQ ID NO: 36

SEQ ID NO: 32 and SEQ ID NO: 36

SEQ ID NO: 30 and SEQ ID NO: 37

SEQ ID NO: 32 and SEQ ID NO: 37

SEQ ID NO: 38 and SEQ ID NO: 43

SEQ ID NO: 40 and SEQ ID NO: 43

SEQ ID NO: 42 and SEQ ID NO: 43

SEQ ID NO: 39 and SEQ ID NO: 44

SEQ ID NO: 41 and SEQ ID NO: 44

SEQ ID NO: 38 and SEQ ID NO: 45

SEQ ID NO: 40 and SEQ ID NO: 45

SEQ ID NO: 42 and SEQ ID NO: 45

SEQ ID NO: 39 and SEQ ID NO: 46

SEQ ID NO: 41 and SEQ ID NO: 46

SEQ ID NO: 38 and SEQ ID NO: 47

SEQ ID NO: 40 and SEQ ID NO: 47

SEQ ID NO: 42 and SEQ ID NO: 47

SEQ ID NO: 49 and SEQ ID NO: 55

SEQ ID NO: 51 and SEQ ID NO: 55

SEQ ID NO: 53 and SEQ ID NO: 55

SEQ ID NO: 48 and SEQ ID NO: 56

SEQ ID NO: 50 and SEQ ID NO: 56

SEQ ID NO: 52 and SEQ ID NO: 56

SEQ ID NO: 54 and SEQ ID NO: 56

SEQ ID NO: 49 and SEQ ID NO: 57

SEQ ID NO: 51 and SEQ ID NO: 57

SEQ ID NO: 53 and SEQ ID NO: 57

3. An anti-LAG-3 antibody, or an antigen-binding portion thereof, capable of binding human LAG-3, wherein the antibody or antigen-binding portion thereof comprises a set of six complementarity determining regions (CDRs), CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, selected from the group consisting of:

CDR-H1 comprising DFNIKDDYMH (residues 26-35 of SEQ ID NO:114), CDR-H2 comprising WIVPENGNTEYASKFQG (residues 50-66 of SEQ ID NO:114), CDR-H3 comprising YGDY (residues 99-102 of SEQ ID NO:114), CDR-L1 comprising RASQEISGYLS (residues 24-34 of SEQ ID NO:117), CDR-L2 comprising AASTLDS (residues 50-56 of SEQ ID NO:117), and CDR-L3 comprising LQYASYPLT (residues 89-97 of SEQ ID NO:117);

CDR-H1 comprising DDYMH (residues 31-35 of SEQ ID NO:135), CDR-H2 comprising WIVPENANTVYASKFQG (SEQ ID NO:224), CDR-H3 comprising YGDY (residues 99-102 of SEQ ID NO:135), CDR-LI comprising RASQEISGYLS (residues 24-34 of SEQ ID NO:138), CDR-L2 comprising AASALDS (residues 50-56 of SEQ ID NO:138), and CDR-L3 comprising LQYASYPLT (residues 89-97 of SEQ ID NO:138);

CDR-H1 comprising DDYMH (residues 31-35 of SEQ ID NO:136), CDR-H2 comprising WIVPRNANTVYASKFQG (SEQ ID NO:225), CDR-H3 comprising YGDY (residues 99-102 of SEQ ID NO:136), CDR-LI comprising RASQEISGYLS (residues 24-34 of SEQ ID NO:139), CDR-L2 comprising AASALDL (residues 50-56 of SEQ ID NO:139), and CDR-L3 comprising LQYASYPLT (residues 89-97 of SEQ ID NO:139); and

CDR-H1 comprising DDYMH (residues 31-35 of SEQ ID NO:136), CDR-H2 comprising WIVPRNANTVYASKFQG (SEQ ID NO:225), CDR-H3 comprising YGDY (residues 99-102 of SEQ ID NO:136), CDR-LI comprising RASQEISGYLS (residues 24-34 of SEQ ID NO:117), CDR-L2 comprising AASTLDS (residues 50-56 of SEQ ID NO:117), and CDR-L3 comprising LQYASYPLT (residues 89-97 of SEQ ID NO:117).

4. An anti-LAG-3 antibody comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH and VL comprise amino acid sequences selected from the group consisting of:

SEQ ID NO: 135 and SEQ ID NO: 138

SEQ ID NO: 136 and SEQ ID NO: 117

SEQ ID NO: 227 and SEQ ID NO: 139

SEQ ID NO: 136 and SEQ ID NO: 139

SEQ ID NO: 226 and SEQ ID NO: 138

SEQ ID NO: 227 and SEQ ID NO: 117

5. A binding protein comprising first, second and third polypeptide chains,

wherein the first polypeptide chain comprises, from amino to carboxyl terminus, (i) VL A -CL-VH B -CH1-Fc wherein CL is directly fused to VH B , or (ii) VH B -CH1-VL A -CL-Fc wherein CH1 is directly fused to VL A ; the second polypeptide chain comprises, from amino to carboxyl terminus, VH A -CH1; and the third polypeptide chain comprises, from amino to carboxyl terminus, VL B -CL;

wherein VL is a light chain variable domain, CL is a light chain constant domain, VH is a heavy chain variable domain, CH1 is a heavy chain constant domain, Fc is an immunoglobulin Fc region, A is an epitope of PD-1 or LAG-3 and B is an epitope of PD-1 or LAG-3, with the proviso that A and B are different, and the binding protein is bispecific and multivalent in being capable of binding to both PD-1 and LAG-3, and

wherein VH A and VL A respectively represent VH LAG3 and VL LAG3 when A is an epitope of LAG-3, or VL B and VH B respectively represent VL LAG3 and VH LAG3 when B is an epitope of LAG-3, and the VH LAG3 and VL LAG3 respectively comprise CDRs (CDR-H1, CDR-H2, CDR-H3, and CDR-L1, CDR-L2, CDR-L3), selected from the group consisting of:

CDR-H1 comprising DDYMH (residues 31-35 of SEQ ID NO:135), CDR-H2 comprising WIVPENANTVYASKFQG (SEQ ID NO:224), CDR-H3 comprising YGDY (residues 99-102 of SEQ ID NO:135), CDR-L1 comprising RASQEISGYLS (residues 24-34 of SEQ ID NO:138), CDR-L2 comprising AASALDS (residues 50-56 of SEQ ID NO:138), and CDR-L3 comprising LQYASYPLT (residues 89-97 of SEQ ID NO:138);

CDR-H1 comprising DDYMH (residues 31-35 of SEQ ID NO:136), CDR-H2 comprising WIVPRNANTVYASKFQG (SEQ ID NO:225), CDR-H3 comprising YGDY (residues 99-102 of SEQ ID NO:136), CDR-L1 comprising RASQEISGYLS (residues 24-34 of SEQ ID NO:139), CDR-L2 comprising AASALDL (residues 50-56 of SEQ ID NO:139), and CDR-L3 comprising LQYASYPLT (residues 89-97 of SEQ ID NO:139); and

CDR-H1 comprising DDYMH (residues 31-35 of SEQ ID NO:136), CDR-H2 comprising WIVPRNANTVYASKFQG (SEQ ID NO:225), CDR-H3 comprising YGDY (residues 99-102 of SEQ ID NO:136), CDR-L1 comprising RASQEISGYLS (residues 24-34 of SEQ ID NO:117), CDR-L2 comprising AASTLDS (residues 50-56 of SEQ ID NO:117), and CDR-L3 comprising LQYASYPLT (residues 89-97 of SEQ ID NO:117).

6. The binding protein of claim 5 , wherein the VL A -CL and VH A -CH1 domains are from a parental antibody capable of binding to one of the antigen targets PD-1 or LAG-3, and the VL B -CL and VH B -CH1 domains are from a different parental antibody capable of binding to the other of the antigen targets PD-1 or LAG-3.

7. The binding protein of claim 6 , comprising first, second and third polypeptide chains, wherein the first polypeptide chain comprises, from amino to carboxyl terminus, VL PD-1 -CL-VH LAG-3 -CH1-Fc wherein CL is directly fused to VH LAG-3 ; the second polypeptide chain comprises, from amino to carboxyl terminus, VH PD-1 -CH1; and the third polypeptide chain comprises, from amino to carboxyl terminus, VL LAG-3 -CL;

wherein VL PD-1 is a light chain variable domain of an anti-PD-1 antibody, CL is a light chain constant domain, VH PD-1 is a heavy chain variable domain of an anti-PD-1 antibody, CH1 is a heavy chain constant domain, VL LAG-3 is a light chain variable domain of an anti-LAG-3 antibody, VH LAG-3 is a heavy chain variable domain of an anti-LAG-3 antibody, and Fc is an immunoglobulin Fc region.

8. The binding protein of claim 7 , wherein, in the first polypeptide chain, the domains VL PD-1 -CL are the same as the light chain of an anti-PD-1 parental antibody, the domains VH PD-1 -CHI are the same as the heavy chain variable and heavy chain constant domains of an anti-PD-1 parental antibody, the domains VL LAG-3 -CL are the same as the light chain of an anti-LAG-3 parental antibody, and the domains VH LAG-3 -CHI are the same as the heavy chain variable and heavy chain constant domains of an anti-LAG-3 parental antibody.

9. The binding protein of claim 6 , comprising first, second and third polypeptide chains, wherein the first polypeptide chain comprises, from amino to carboxyl terminus, VL LAG-3 -CL-VH PD-1 -CH1-Fc wherein CL is directly fused to VH PD-1 ; the second polypeptide chain comprises, from amino to carboxyl terminus, VH LAG-3 -CH1; and the third polypeptide chain comprises, from amino to carboxyl terminus, VL PD-1 -CL;

10. The binding protein of claim 9 , wherein, in the first polypeptide chain, the domains VL LAG-3 -CL are the same as the light chain of an anti-LAG-3 parental antibody, the domains VH LAG-3 -CHI are the same as the heavy chain variable and heavy chain constant domains of an anti-LAG-3 parental antibody, the domains VL PD-1 -CL are the same as the light chain of an anti-PD-1 parental antibody, and the domains VH PD-1 -CHI are the same as the heavy chain variable and heavy chain constant domains of an anti-PD-1 parental antibody.

11. The binding protein of claim 5 , further comprising an Fc region comprising SEQ ID NO:28.

12. The binding protein of claim 5 , wherein

the first polypeptide chain comprises an amino acid sequence of amino acids 23-679 of SEQ ID NO:182; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:186; and the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:188;

the first polypeptide chain comprises an amino acid sequence of amino acids 23-687 of SEQ ID NO:189; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:193; and the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:195;

the first polypeptide chain comprises an amino acid sequence of amino acids 23-679 of SEQ ID NO:196; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:200; and the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:202;

the first polypeptide chain comprises an amino acid sequence of amino acids 23-687 of SEQ ID NO:203; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:207; and the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:209;

the first polypeptide chain comprises an amino acid sequence of amino acids 23-679 of SEQ ID NO:210; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:214; and the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:216; or

the first polypeptide chain comprises an amino acid sequence of amino acids 23-687 of SEQ ID NO:217; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:221; and the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:223.

13. A pharmaceutical composition comprising at least one anti-PD-1 antibody or antigen-binding portion thereof of claim 1 , and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising at least one anti-LAG-3 antibody or antigen-binding portion thereof of claim 1 , and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising at least one binding protein of claim 5 , and a pharmaceutically acceptable carrier.

16. A method of treating a disorder in which PD-1-mediated and/or LAG-3-mediated activity is detrimental, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of claim 13 .

17. A method of treating a disorder in which PD-1-mediated and/or LAG-3-mediated activity is detrimental, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of claim 14 .

18. A method of treating a disorder in which PD-1-mediated and/or LAG-3-mediated activity is detrimental, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of claim 15 .

19. The method of claim 18 , wherein the disorder is cancer, and the cancer is a melanoma, a renal cancer, a prostate cancer, a pancreatic adenocarcinoma, a breast cancer, a colon cancer, a lung cancer, an esophageal cancer, a squamous cell carcinoma of the head and neck, a liver cancer, an ovarian cancer, a cervical cancer, a thyroid cancer, a glioblastoma, a glioma, a leukemia, a lymphoma, or a primary bone cancer.

20. The method of claim 19 , wherein the melanoma is a metastatic malignant melanoma; the renal cancer is a clear cell carcinoma; the prostate cancer is a hormone refractory prostate adenocarcinoma; the lung cancer is a non-small cell lung cancer; and/or the primary bone cancer is an osteosarcoma, Ewing sarcoma, malignant fibrous histiocytoma, or chondrosarcoma.

21. The method of claim 18 , wherein the subject is a human.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 26, 2024

From: WU, XUAN; GONG, SHIYONG; WU, CHENGBIN

To: SHANGHAI EPIMAB BIOTHERAPEUTICS LTD.

Reel/Frame 067844/0008 →

Priority Claims (1)

WO PCT/CN2018/085468 · May 3, 2018 · international

Continuity (1)

Related Publication 20210188980A1 · Jun 24, 2021

Cited By (2)

US 12,263,234 US 12,448,443