# US 2020/0399375 A1 · Pd-l1 antibody, antigen-binding fragment thereof and medical application thereof

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- Number: US 2020/0399375 A1
- Document ID: US20200399375A1
- Status: Published application
- Kind: A1
- Application number: 16/947,583
- Filed: 2020-08-07
- Published: 2020-12-24
- Earliest claimed: 2015-11-17
- Assignees: Suzhou Suncadia Biopharmaceuticals Co., Ltd.; Jiangsu Hengrui Medicine Co., Ltd.; Shanghai Hengrui Pharmaceutical Co., Ltd.
- Applicants: Suzhou Suncadia Biopharmaceuticals Co., Ltd.; Jiangsu Hengrui Medicine Co., Ltd.; Shanghai Hengrui Pharmaceutical Co., Ltd.
- Inventors: Xiangdong Qu; Qiyue Hu; Shaoyu Xu; Dongbing Cui; Houcong Jin; Weikang Tao; Lianshan Zhang; Guoqing Cao; Piaoyang Sun
- Web page: https://patentgrep.com/patent/US20200399375A1

## CPC

- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61P 35/00: Antineoplastic agents
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61K 2039/505: {comprising antibodies}
- A61K 2039/572: {cytotoxic response}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/40: characterized by post-translational modification
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a PD-L1 antibody, antigen-binding fragments, and medical application thereof. Further, the present invention relates to chimeric antibodies and humanized antibodies comprising the CDR regions of the present PD-L1 antibody, as well as a pharmaceutical composition comprising the present PD-L1 antibody and the antigen-binding fragments thereof, and their use as anti-cancer drugs. In particular, the present invention relates to a humanized PD-L1 antibody and its use in preparation of a medicament for the treatment of PD-L1 mediated disease or disorder.

## Claims

### Claim 1

A method for treating a PD-L1 mediated disease or disorder in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, comprising: a heavy chain variable region comprising:
a heavy chain CDR1 (HCDR1) of NDYWX1 (SEQ ID NO: 10) or SYWMH (SEQ ID NO: 16);
a heavy chain CDR2 (HCDR2) of YISYTGSTYYNPSLKS (SEQ ID NO: 11) or RIX4PNSG X5TSYNEKFKN (SEQ ID NO: 17); and
a heavy chain CDR3 (HCDR3) of SGGWLAPFDY (SEQ ID NO: 12) or GGSSYDYFDY (SEQ ID NO: 18); and
a light chain variable region comprising:
a light chain CDR1 (LCDR1) of KSSQSLFYX2SNQKX3SLA (SEQ ID NO: 13) or RASESVSIHGTHLMH (SEQ ID NO: 19);
a light chain CDR2 (LCDR2) of GASTRES (SEQ ID NO: 14) or AASNLES (SEQ ID NO: 20); and
a light chain CDR3 (LCDR3) of QQYYGYPYT (SEQ ID NO: 15) or QQSFEDPLT (SEQ ID NO: 21);
wherein X is N or T, X2 is R or H, X3 is N or H, X4 is H or G, and X5 is G or F.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the disease or disorder is cancer.

### Claim 3 (depends on 2)

The method according to claim 2, wherein the cancer is a PD-L1-expressing cancer selected from the group consisting of breast cancer, lung cancer, stomach cancer, intestinal cancer, renal cancer, melanoma, non-small cell lung cancer and bladder cancer; and most preferably is selected from the group consisting of non-small cell lung cancer, melanoma, bladder cancer and renal cancer.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the heavy chain variable region comprises the HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, respectively; or SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, respectively.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the light chain variable region comprises the LCDR1, LCDR2 and LCDR3 of SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively; or SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21, respectively.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the antibody light chain variable region further comprises a light chain framework (FR) region derived from murine κ chain, or murine λ-chain; and the antibody heavy chain variable region further comprises a heavy chain FR region derived from murine IgG1, murine IgG2 or murine IgG3.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the antibody heavy chain variable region contains the heavy chain FR region derived from a murine heavy chain variable region having the amino acid sequence selected from the group consisting of SEQ ID NOs: 6 and 8, and the antibody light chain variable region contains a light chain FR region derived from a murine light chain variable region having the amino acid sequence selected from the group consisting of SEQ ID NOs: 7 and 9.

### Claim 8 (depends on 6)

The method according to claim 6, wherein the antibody light chain further comprises a light chain constant region derived from murine κ chain, or a light chain constant region derived from murine λ chain; wherein the antibody heavy chain further comprises a heavy chain constant region derived from murine IgG1, or a heavy chain constant region derived from murine IgG2, or a heavy chain constant region derived from murine IgG3.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the antibody or the antigen-binding fragment thereof is a chimeric antibody or a humanized antibody or a fragment thereof.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the humanized antibody is the humanized antibody 9-2 or the humanized antibody 24D5, the heavy chain framework (FR) sequence on the heavy chain variable region of the humanized antibody 9-2 is derived from a combination sequence of a human germline heavy chain IGHV4-30-4*01 and human germline heavy chain hjh2, and comprises FR1, FR2, and FR3 from human germline heavy chain IGHV4-30-4*01 and FR4 from hjh2; or
the heavy chain FR sequence on the heavy chain variable region of the humanized antibody 24D5 is derived from a combination sequence of human germline heavy chain IGHV1-46*01 and human germline heavy chain hjh6.1, and comprises FR1, FR2 and FR3 from human germline heavy chain IGHV1-46*01 and FR4 from hjh6.1.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the heavy chain FR sequence of the humanized antibody 9-2 has 1-8 amino acid back-mutations selected from the group consisting of W47Y, V71R, G27Y, I48M, V67L, F78Y, S30T and Q39K; wherein the heavy chain FR sequence of the humanized antibody 24D5 has 1-8 amino acid back-mutations selected from the group consisting of T74K, R72V, M48I, M70L, R38Q, L83F, V68A, and V79A.

### Claim 12 (depends on 10)

The method according to claim 10, wherein the heavy chain variable region sequence of the humanized antibody 9-2 comprises SEQ ID NO: 22 or a variant thereof, wherein the variant comprises 1-8 amino acid back-mutations selected from the group consisting of W47Y, V71R, G27Y, I48M, V67L, F78Y, S30T and Q39K; or the heavy chain variable region sequence of the humanized antibody 24D5 comprises SEQ ID NO: 24 or a variant thereof, wherein the variant comprises 1-8 amino acid back-mutations selected from the group consisting of T74K, R72V, M48I, M70L, R38Q, L83F, V68A, and V79A.

### Claim 13 (depends on 9)

The method according to claim 9, wherein the humanized antibody is the humanized antibody 9-2 or the humanized antibody 24D5, wherein:
the light chain framework (FR) sequence on the light chain variable region of the humanized antibody 9-2 is derived from a combination sequence of a human germline light chain IGKV4-1*01 and human germline light chain hjk4.1, and comprises FR1, FR2 and FR3 from human germline light chain IGKV4-1*01 and FR4 from hjk4.1, or
the light chain FR sequence of the light chain variable region of the humanized antibody 24D5 is derived from a combination sequence of a human germline light chain IGKV7-3*01 and human germline light chain hjh2.1, and comprises FR1, FR2 and FR3 from IGKV7-3*01 and FR4 from hjk2.1.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the light chain FR sequence of the humanized antibody 9-2 has a P49S amino acid back-mutation; wherein the light chain FR sequence of the humanized antibody 24D5 has 1-3 amino acid back-mutations selected from the group consisting of Y91F, T22S and G72E, and optionally an N85E deglycosylation mutation.

### Claim 15 (depends on 13)

The method according to claim 13, wherein the light chain variable region sequence of the humanized antibody 9-2 comprises the amino acid sequence of SEQ ID NO: 23 or a variant thereof, wherein the variant comprises a P49S amino acid back-mutation; or the light chain variable region sequence of the humanized antibody 24D5 comprises the amino acid sequence of SEQ ID NO: 25 or a variant thereof, wherein the variant comprises 1-3 amino acid back-mutations selected from the group consisting of Y91F, T22S and G72E, and optionally an N85E deglycosylation mutation.

### Claim 16 (depends on 9)

The method according to claim 9, wherein X1 is T, X2 is H, X3 is H, X4 is G, and X5 is F.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the heavy chain variable region sequence of the humanized antibody 9-2 comprises SEQ ID NO: 26 and the light chain variable region sequence of the humanized antibody 9-2 comprises SEQ ID NO: 27; or
the heavy chain variable region sequence of the humanized antibody 24D5 comprises SEQ ID NO: 28 and the light chain variable region sequence of the humanized antibody 24D5 comprises SEQ ID NO: 29.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the heavy chain of the humanized antibody further comprises a heavy chain constant region derived from human IgG1, IgG2, IgG3, or IgG4; wherein the light chain of the humanized antibody further comprises a constant region derived from human κ chain, or human λ chain.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the heavy chain constant region comprises IgG4 heavy chain constant region with F234A and L235A mutations.

### Claim 20 (depends on 18)

The method according to claim 18, wherein the humanized antibody 9-2 comprises the heavy chain sequence of SEQ ID NO: 30 and the light chain sequence of SEQ ID NO: 32; wherein the humanized antibody 24D5 comprises the heavy chain sequence of SEQ ID NO: 34 and the light chain sequence of SEQ ID NO: 36.

### Claim 21

A method for treating a PD-L1 mediated disease or disorder in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
(i) the heavy chain variable region comprises a heavy chain CDR1 (HCDR1) of NDYWX1 (SEQ ID NO: 10), a heavy chain CDR2 (HCDR2) of YISYTGSTYYNPSLKS (SEQ ID NO: 11) and a heavy chain CDR3 (HCDR3) of SGGWLAPFDY (SEQ ID NO: 12); and
the light chain variable region comprises a light chain CDR1 (LCDR1) of KSSQSLFYX2SNQKX3SLA (SEQ ID NO: 13), a light chain CDR2 (LCDR2) of GASTRES (SEQ ID NO: 14) and a light chain CDR3 (LCDR3) of QQYYGYPYT (SEQ ID NO: 15);
wherein X1 is T, X2 is H and X3 is H;
or
(ii) the heavy chain variable region comprises a heavy chain CDR1 (HCDR1) of SYWMH (SEQ ID NO: 16), a heavy chain CDR2 (HCDR2) of RIX4PNSG X5TSYNEKFKN (SEQ ID NO: 17) and a heavy chain CDR3 (HCDR3) of GGSSYDYFDY (SEQ ID NO: 18); and
the light chain variable region comprises a light chain CDR1 (LCDR1) of RASESVSIHGTHLMH (SEQ ID NO: 19), a light chain CDR2 (LCDR2) of AASNLES (SEQ ID NO: 20) and a light chain CDR3 (LCDR3) of QQSFEDPLT (SEQ ID NO: 21);
wherein X4 is G, and X5 is F.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the disease or disorder is a cancer.

### Claim 23 (depends on 22)

The method according to claim 22, wherein the cancer is a PD-L1-expressing cancer selected from the group consisting of breast cancer, lung cancer, stomach cancer, intestinal cancer, renal cancer, melanoma, non-small cell lung cancer and bladder cancer.