IP Library › Granted Patent US 12,534,531
Granted Patent B2
US 12,534,531 · App. 18/114,109 · Granted Jan 27, 2026

PD-1-binding molecules and methods of use thereof

Inventors: Kalpana Shah (Boyds, MD); Douglas H. Smith (San Mateo, CA); Ross La Motte-Mohs (Boyds, MD); Leslie S. Johnson (Darnestown, MD); Paul A. Moore (North Potomac, MD); Ezio Bonvini (Potomac, MD); Scott Koenig (Rockville, MD)
Assignee: MacroGenics, Inc.
C07K16/2818C07K16/2803C07K2317/24C07K2317/31C07K2317/33C07K2317/52C07K2317/76C07K2317/92
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Quick Facts
Patent No.
US 12,534,531
App. No.
18/114,109
Granted
Jan 27, 2026
Kind
B2
Abstract

The present invention is directed to selected anti-PD-1 antibodies capable of binding to both cynomolgus monkey PD-1 and to human PD-1: PD-1 mAb 1, PD-1 mAb 2, PD-1 mAb 3, PD-1 mAb 4, PD-1 mAb 5, PD-1 mAb 6, PD-1 mAb 7, PD-1 mAb 8, PD-1 mAb 9, PD-1 mAb 10, PD-1 mAb 11, PD-1 mAb 12, PD-1 mAb 13, PD-1 mAb 14, or PD-1 mAb 15, and to humanized and chimeric versions of such antibodies. The invention additionally pertains to PD-1-binding molecules that comprise PD-1 binding fragments of such anti-PD-1 antibodies, immunocongugates, and to bispecific molecules, including diabodies, BiTEs, bispecific antibodies, etc., that comprise (i) such PD-1-binding fragments, and (ii) a domain capable of binding an epitope of a molecule involved in regulating an immune check point present on the surface of an immune cells. The present invention also pertains to methods of using molecules that bind PD-1 for stimulating immune responses, as well as methods of detecting PD-1.

Claims (36)

1 . A method of treating a cancer in a subject in need thereof, comprising administering to the subject:

(a) an anti-human PD-1-binding monospecific monoclonal antibody that comprises a Variable Heavy Chain Domain and a Variable Light Chain Domain, wherein:

(i) the Variable Heavy Chain Domain comprises a CDR H 1 Domain, a CDR H 2 Domain and a CDR H 3 Domain, and the Variable Light Chain Domain comprises a CDR L 1 Domain, a CDR L 2 Domain, and a CDR L 3 Domain,

(ii) the CDR H 1 Domain, CDR H 2 Domain, and CDR H 3 Domain are the Heavy Chain CDRs of hPD-1 mAb 7 (1.2), and respectively have the amino acid sequences: SEQ ID NO: 139, SEQ ID NO: 140, and SEQ ID NO: 141, and

(iii) the CDR L 1 Domain, CDR L 2 Domain, and CDR L 3 Domain are the Light Chain CDRs of hPD-1 mAb 7 (1.2), and, respectively have the amino acid sequences: SEQ ID NO:157, SEQ ID NO:145, and SEQ ID NO:146; and

(b) one or more additional molecules that are effective in stimulating an immune response or that specifically bind a cancer antigen, wherein the cancer expresses PD-L1.

2 . The method of claim 1 , wherein the Variable Heavy Chain Domain comprises the amino acid sequence of SEQ ID NO: 147.

3 . The method of claim 1 , wherein the Variable Light Chain Domain comprises the amino acid sequence of SEQ ID NO:153.

4 . The method of claim 1 , wherein the Variable Heavy Chain Domain comprises the amino acid sequence of SEQ ID NO:147, and the Variable Light Chain Domain comprises the amino acid sequence of SEQ ID NO: 153.

5 . The method of claim 1 , wherein the antibody is a chimeric antibody or a humanized antibody.

6 . The method of claim 1 , wherein the antibody comprises an Fc Region.

7 . The method of claim 6 , wherein the Fc Region is of the IgG1, IgG2, IgG3, or IgG4 isotype.

8 . The method of claim 7 , wherein the antibody further comprises a Hinge Domain.

9 . The method of claim 8 , wherein the Fc Region and the Hinge Doman are of the IgG4 isotype, and the Hinge Domain comprises a stabilizing mutation.

10 . The method of claim 6 , wherein the antibody comprises SEQ ID NOs: 264 and 265.

11 . The method of claim 6 , wherein the antibody comprises SEQ ID NOs: 264 and 266.

12 . The method of claim 6 , wherein the Fc Region is a variant Fc Region that comprises:

(a) one or more amino acid modifications that reduces the affinity of the variant Fc Region for an FcγR; and/or

(b) one or more amino acid modifications that enhances the serum half-life of the variant Fc Region.

13 . The method of claim 12 , wherein the modifications that reduce the affinity of the variant Fc Region for an FcγR comprise the substitution of L234A; L235A; or L234A and L235A, wherein the numbering is that of the EU index as in Kabat.

14 . The method of claim 12 , wherein the modifications that that enhance the serum half-life of the variant Fc Region comprise the substitution of M252Y; M252Y and S254T; M252Y and T256E; M252Y, S254T and T256E; or K288D and H435K, wherein the numbering is that of the EU index as in Kabat.

15 . The method of claim 1 , wherein the one or more additional molecules that are effective in stimulating an immune response are an anti-CD137 antibody, an anti-CTLA-4 antibody, an anti-OX40 antibody, an anti-LAG-3 antibody, an anti-PD-L1 antibody, an anti-TIGIT antibody, anti-TIM-3 antibody, and/or a cancer vaccine.

16 . The claim 1 , wherein the cancer antigen is 5T4, B7H3, CD19, CD20, CD51, CD123, DR5, EGFR, EpCam, GD2, gpA33, HER2, ROR-1, TAG-72, VEGF-A, and/or VEGFR2.

17 . The method of claim 1 , wherein the cancer is selected from the group consisting of an adrenal gland tumor, an AIDS-associated cancer, an alveolar soft part sarcoma, an astrocytic tumor, bladder cancer, bone cancer, a brain and spinal cord cancer, a metastatic brain tumor, a breast cancer, a carotid body tumors, a cervical cancer, a chondrosarcoma, a chordoma, a chromophobe renal cell carcinoma, a clear cell carcinoma, a colon cancer, a colorectal cancer, a cutaneous benign fibrous histiocytoma, a desmoplastic small round cell tumor, an ependymoma, a Ewing's tumor, an extraskeletal myxoid chondrosarcoma, a fibrogenesis imperfecta ossium, a fibrous dysplasia of the bone, a gallbladder or bile duct cancer, gastric cancer, a gestational trophoblastic disease, a germ cell tumor, a head and neck cancer, hepatocellular carcinoma, an islet cell tumor, a Kaposi's Sarcoma, a kidney cancer, a leukemia, a lipoma/benign lipomatous tumor, a liposarcoma/malignant lipomatous tumor, a liver cancer, a lymphoma, a lung cancer, a medulloblastoma, a melanoma, a meningioma, a multiple endocrine neoplasia, a multiple myeloma, a myelodysplastic syndrome, a neuroblastoma, a neuroendocrine tumors, an ovarian cancer, a pancreatic cancer, a papillary thyroid carcinoma, a parathyroid tumor, a pediatric cancer, a peripheral nerve sheath tumor, a phaeochromocytoma, a pituitary tumor, a prostate cancer, a posterious uveal melanoma, a rare hematologic disorder, a renal metastatic cancer, a rhabdoid tumor, a rhabdomysarcoma, a sarcoma, a skin cancer, a soft-tissue sarcoma, a squamous cell cancer, a stomach cancer, a synovial sarcoma, a testicular cancer, a thymic carcinoma, a thymoma, a thyroid metastatic cancer, and a uterine cancer.

18 . The method of claim 1 , wherein the cancer is colorectal cancer, hepatocellular carcinoma, glioma, kidney cancer, breast cancer, multiple myeloma, bladder cancer, neuroblastoma; sarcoma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute B lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), non-Hodgkin's lymphomas (NHL), including mantel cell leukemia (MCL), and small lymphocytic lymphoma (SLL), Hodgkin's lymphoma, systemic mastocytosis, or Burkitt's lymphoma.

19 . The method of claim 1 , wherein the cancer is a uterine cancer.

20 . The method of claim 1 , wherein the cancer is a squamous cell cancer.

21 . The method of claim 1 , wherein the cancer is glioma.

22 . The method of claim 1 , wherein the cancer is a cervical cancer.

23 . The method of claim 1 , wherein the cancer is kidney cancer.

24 . The method of claim 1 , wherein the cancer is a lung cancer.

25 . The method of claim 1 , wherein the cancer is non-small cell lung cancer.

26 . The method of claim 1 , wherein the cancer is a head and neck cancer.

27 . The method of claim 1 , wherein the cancer is a renal metastatic cancer.

28 . The method of claim 1 , wherein the cancer is a chromophobe renal cell carcinoma.

29 . The method of claim 1 , wherein the cancer is skin cancer.

Continuity (7)
Continuation 16752464 · Jan 24, 2020
Continuation 15748458
Provisional Application 62322974 · Apr 15, 2016
Provisional Application 62255140 · Nov 13, 2015
Provisional Application 62239559 · Oct 9, 2015
Provisional Application 62198867 · Jul 30, 2015
Related Publication 20230357404A1 · Nov 9, 2023
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