# US 10,765,743 B2 · Antibodies binding AXL

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- Number: US 10,765,743 B2
- Document ID: US10765743B2
- Status: Granted
- Kind: B2
- Application number: 16/248,402
- Filed: 2019-01-15
- Published: 2019-09-12
- Granted: 2020-09-08
- Earliest claimed: 2014-07-11
- Assignees: Genmab A/S
- Applicants: Genmab A/S
- Inventors: Esther Breij; David Satijn; Edward Norbert Van Den Brink; Dennis Verzijl; Rob N. De Jong; Paul Parren; Riemke Van Dijkhuizen Radersma
- Web page: https://patentgrep.com/patent/US10765743B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 47/6801: {Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6857: {the tumour determinant being from lung cancer cell}
- A61K 47/6869: {the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/3061: {Blood cells}
- A61K 2039/505: {comprising antibodies}
- A61K 2121/00: Preparations for use in therapy
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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
- 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)

## Abstract

The present invention relates to anti-AXL antibodies, immunoconjugates, compositions and method of treatment of cancer with such anti-AXL antibodies, immunoconjugates, or compositions.

## Claims

### Claim 1

A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate comprising a cytotoxic agent and an antibody which binds to human AXL and comprises a heavy chain variable (VH) region and a light chain variable (VL) region selected from the group consisting of:
a) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, GAS, and SEQ ID NO: 40, respectively,
b) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, GAS, and SEQ ID NO: 97, respectively, and
c) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 101, DAS, and SEQ ID NO: 102, respectively.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, GAS, and SEQ ID NO: 40, respectively.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, GAS, and SEQ ID NO: 97, respectively.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 101, DAS, and SEQ ID NO: 102, respectively.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody comprises a VH region and a VL region selected from the group consisting of:
a) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 2,
b) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 26, and
c) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28.

### Claim 6 (depends on 5)

The method of claim 5, wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 2.

### Claim 7 (depends on 5)

The method of claim 5, wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 26.

### Claim 8 (depends on 5)

The method of claim 5, wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28.

### Claim 9 (depends on 1)

The method of claim 1, wherein the antibody binds to;
an epitope within the Ig1-like domain of human AXL, wherein said epitope comprises or requires one or more amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL, and wherein the numbering of positions are in relation to human AXL having the amino acid sequence set forth in SEQ ID NO: 130.

### Claim 10 (depends on 1)

The method of claim 1, wherein the antibody comprises a heavy chain of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

### Claim 11 (depends on 1)

The method of claim 1, wherein the antibody is an ADCC-deficient antibody, a stabilized IgG4 antibody or a monovalent antibody.

### Claim 12 (depends on 1)

The method of claim 1, wherein the antibody is a single chain antibody.

### Claim 13 (depends on 1)

The method of claim 1, wherein the cytotoxic agent is MMAE.

### Claim 14 (depends on 1)

The method of claim 1, wherein the cytotoxic agent is linked to said antibody with a cleavable linker.

### Claim 15 (depends on 14)

The method of claim 14, wherein the linker is mc-vc-PAB.

### Claim 16 (depends on 1)

The method of claim 1, wherein the cytotoxic agent is MMAE and the linker is mc-vc-PAB.

### Claim 17 (depends on 1)

The method of claim 1, wherein the cancer is a solid tumor expressing AXL or an AXL-expressing hematological cancer.

### Claim 18 (depends on 1)

The method according to claim 1, wherein the cancer is selected from the group consisting of colorectal cancer, bladder cancer, bone cancer, breast cancer, cancers of the central nervous system, cervical cancer, connective tissue cancer, endometrium cancer, epidermoid carcinoma, fibroblast cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, muscle cancer, neural tissue cancer, ovarian cancer, pancreatic cancer, skin cancer, and soft tissue sarcoma.

### Claim 19 (depends on 18)

The method of claim 18, wherein the cancer is lung cancer.

### Claim 20 (depends on 18)

The method of claim 18, wherein the cancer is skin cancer.

### Claim 21 (depends on 18)

The method of claim 18, wherein the cancer is a sarcoma.

### Claim 22 (depends on 18)

The method of claim 18, wherein the cancer is cervical cancer.

### Claim 23 (depends on 18)

The method of claim 18, wherein the cancer is endometrium cancer.

### Claim 24 (depends on 18)

The method of claim 18, wherein the cancer is ovarian cancer.

### Claim 25

A method for inhibiting growth and/or proliferation of a tumor cell expressing AXL, comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate comprising a cytotoxic agent and an antibody which binds to human AXL and comprises a heavy chain variable (VH) region and a light chain variable (VL) region selected from the group consisting of:
a) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, GAS, and SEQ ID NO: 40, respectively,
b) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, GAS, and SEQ ID NO: 97, respectively, and
c) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 101, DAS, and SEQ ID NO: 102, respectively.

### Claim 26 (depends on 25)

The method of claim 25, wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, GAS, and SEQ ID NO: 40, respectively.

### Claim 27 (depends on 25)

The method of claim 25, wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, GAS, and SEQ ID NO: 97, respectively.

### Claim 28 (depends on 25)

The method of claim 25, wherein the antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 101, DAS, and SEQ ID NO: 102, respectively.

### Claim 29 (depends on 25)

The method of claim 25, wherein the antibody comprises a VH region and a VL region selected from the group consisting of:
a) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 2,
b) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 26, and
c) a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28.

### Claim 30 (depends on 29)

The method of claim 29, wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 1 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 2.

### Claim 31 (depends on 29)

The method of claim 29, wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 25 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 26.

### Claim 32 (depends on 29)

The method of claim 29, wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 28.

### Claim 33 (depends on 25)

The method of claim 25, wherein the antibody binds to an epitope within the Ig1-like domain of human AXL, wherein said epitope comprises one or more amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL, and wherein the numbering of positions are in relation to human AXL having the amino acid sequence set forth in SEQ ID NO: 130.

### Claim 34 (depends on 25)

The method of claim 25, wherein the antibody comprises a heavy chain of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

### Claim 35 (depends on 25)

The method of claim 25, wherein the antibody is an ADCC-deficient antibody, a stabilized IgG4 antibody or a monovalent antibody.

### Claim 36 (depends on 25)

The method of claim 25, wherein the antibody is a single chain antibody.

### Claim 37 (depends on 25)

The method of claim 25, wherein the cytotoxic agent is MMAE.

### Claim 38 (depends on 25)

The method of claim 25, wherein the cytotoxic agent is linked to said antibody with a cleavable linker.

### Claim 39 (depends on 38)

The method of claim 38, wherein the linker is mc-vc-PAB.

### Claim 40 (depends on 39)

The method of claim 39, wherein the cytotoxic agent is MMAE and the linker is mc-vc-PAB.

### Claim 41 (depends on 25)

The method of claim 25, wherein the tumor cell is from a solid tumor expressing AXL or an AXL-expressing hematological cancer.

### Claim 42 (depends on 25)

The method according to claim 25, wherein the tumor cell is from a cancer selected from the group consisting of colorectal cancer, bladder cancer, bone cancer, breast cancer, cancers of the central nervous system, cervical cancer, connective tissue cancer, endometrium cancer, epidermoid carcinoma, fibroblast cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, muscle cancer, neural tissue cancer, ovarian cancer, pancreatic cancer, skin cancer, and soft tissue sarcoma.

### Claim 43

A method for inhibiting growth and/or proliferation of a tumor cell expressing AXL comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate comprising (a) a cytotoxic agent and an antibody which binds to human AXL and comprises variable heavy chain (VH) CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 36, 37, and 38, respectively, and variable light chain (VL) CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 39, GAS, and SEQ ID NO: 40, wherein the cytotoxic agent is MMAE, and wherein the MMAE is linked to the antibody with a mc-vc-PAB linker.

### Claim 44 (depends on 43)

The method of claim 43, wherein the antibody comprises VH and VL regions comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 2, respectively.

### Claim 45

A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate comprising a cytotoxic agent and an antibody which binds to human AXL and comprises the variable heavy chain (VH) CDR1, CDR2, and CDR3 sequences set forth in SEQ ID Nos: 36, 37, and 38, respectively, and the variable light chain (VL) CDR1, CDR2, and CDR3 sequences set forth in SEQ ID No: 39, GAS, and SEQ ID No: 40, wherein the cytotoxic agent is MMAE, and wherein the MMAE is linked to the antibody with a mc-vc-PAB linker.

### Claim 46 (depends on 45)

The method of claim 45, wherein the antibody comprises VH and VL regions comprising the amino acid sequences set forth in SEQ ID Nos: 1 and 2, respectively.