# US 2023/0265183 A1 · Antibody against nectin-4 and application thereof

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- Number: US 2023/0265183 A1
- Document ID: US20230265183A1
- Status: Published application
- Kind: A1
- Application number: 17/996,403
- Filed: 2021-04-21
- Published: 2023-08-24
- Earliest claimed: 2020-04-21
- Assignees: Mabwell (Shanghai) Bioscience Co., Ltd.
- Applicants: Mabwell (Shanghai) Bioscience Co., Ltd.
- Inventors: Hongyuan REN; Jian ZHU; Jian LIN; Lichun WANG; Xiaohong XU; Xiaofang DENG; Jianjun BI; Jin WANG; Jian WU
- Web page: https://patentgrep.com/patent/US20230265183A1

## CPC

- C07K 16/2803: {against the immunoglobulin superfamily}
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/6817: {Toxins}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6877: {the antibody being an immunoglobulin containing regions, domains or residues from different species}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 35/00: Antineoplastic agents
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/77: Internalization into the cell
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Provided is an antibody molecule that binds to human Nectin-4 or a fragment thereof. The antibody is obtained by means of hybridoma screening and humanization techniques, and is used for the prevention or treatment of a cancer, and may be used as a clinical lead drug molecule.

## Claims

### Claim 1

An antibody molecule or fragment thereof, which comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising a combination of heavy and light chain CDRs selected from:
(1) CDR-H1 (GYTFTTY), CDR-H2 (YPGNVN), and CDR-H3 (GLYYFDY) as shown in SEQ ID NOs: 35, 39, and 43; and, CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRYT), and CDR-L3 (QQDYSSPYT) as shown in SEQ ID NOs: 45, 47, and 49;
(2) CDR-H1 (GYTFTTYYIH), CDR-H2 (WIYPGNVNTK), and CDR-H3 (GLYYFDY) as shown in SEQ ID NOs: 36, 40, and 43; and, CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRYT), and CDR-L3 (QQDYSSPYT) as shown in SEQ ID NOs: 45, 47, and 49;
(3) CDR-H1 (TYYIH), CDR-H2 (WIYPGNVNTKYNEKFKG), and CDR-H3 (GLYYFDY) as shown in SEQ ID NOs: 37, 41, and 43; and, CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRYT), and CDR-L3 (QQDYSSPYT) as shown in SEQ ID NOs: 45, 47, and 49;
(4) CDR-H1 (TTYYIH), CDR-H2 (WIGWIYPGNVNTK), and CDR-H3 (ARGLYYFD) as shown in SEQ ID NOs: 38, 42, and 44; and, CDR-L1 (SNDVAWY), CDR-L2 (LLIYYASNRY), and CDR-L3 (QQDYSSPY) as shown in SEQ ID NOs: 46, 48, and 50;
(5) CDR-H1 (GFSLIDY), CDR-H2 (WGDGK), and CDR-H3 (QGGLLFYAMDY) as shown in SEQ ID NOs: 51, 55, and 59; and, CDR-L1 (KSSQSLLNSYSQKNYLA), CDR-L2 (FASTRES), and CDR-L3 (QQHYNTPFT) as shown in SEQ ID NOs: 61, 63, and 65;
(6) CDR-H1 (GFSLIDYGVS), CDR-H2 (VIWGDGKIY), and CDR-H3 (QGGLLFYAMDY) as shown in SEQ ID NOs: 52, 56, and 59; and, CDR-L1 (KSSQSLLNSYSQKNYLA), CDR-L2 (FASTRES), and CDR-L3 (QQHYNTPFT) as shown in SEQ ID NOs: 61, 63, and 65;
(7) CDR-H1 (DYGVS), CDR-H2 (VIWGDGKIYYNSVLKS), and CDR-H3 (QGGLLFYAMDY) as shown in SEQ ID NOs: 53, 57, and 59; and, CDR-L1 (KSSQSLLNSYSQKNYLA), CDR-L2 (FASTRES), and CDR-L3 (QQHYNTPFT) as shown in SEQ ID NOs: 61, 63, and 65;
(8) CDR-H1 (IDYGVS), CDR-H2 (WLGVIWGDGKIY), and CDR-H3 (AKQGGLLFYAMD) as shown in SEQ ID NOs: 54, 58, and 60; and, CDR-L1 (LNSYSQKNYLAWY), CDR-L2 (LLIYFASTRE), and CDR-L3 (QQHYNTPF) as shown in SEQ ID NOs: 62, 64, and 66;
(9) CDR-H1 (GFSLIDY), CDR-H2 (WGDGK), and CDR-H3 (QGGLLFYAMDY) as shown in SEQ ID NOs: 51, 55, and 59; and, CDR-L1 (KSSQSLLNTYSQKNYLA), CDR-L2 (FASTRES), and CDR-L3 (QQHYNTPFT) as shown in SEQ ID NOs: 67, 63, and 65;
(10) CDR-H1 (GFSLIDY), CDR-H2 (WGDAK), and CDR-H3 (QGGLLFYAMDY) as shown in SEQ ID NOs: 51, 68, and 59; and, CDR-L1 (KSSQSLLNTYSQKNYLA), CDR-L2 (FASTRES), and CDR-L3 (QQHYNTPFT) as shown in SEQ ID NOs: 67, 63, and 65;
(11) CDR-H1 (GFSLIDY), CDR-H2 (WGGGK), and CDR-H3 (QGGLLFYAMDY) as shown in SEQ ID NOs: 51, 69, and 59; and, CDR-L1 (KSSQSLLNTYSQKNYLA), CDR-L2 (FASTRES), and CDR-L3 (QQHYNTPFT) as shown in SEQ ID NOs: 67, 63, 65;
(12) CDR-H1 (GYTFTSY), CDR-H2 (YPGNAN), and CDR-H3 (SVYYFDY) as shown in SEQ ID NOs: 70, 74, and 78; and, CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRNT), and CDR-L3 (QQDYSSPYT) as shown in SEQ ID NOs: 45, 80, and 49;
(13) CDR-H1 (GYTFTSYYIH), CDR-H2 (WIYPGNANNK), and CDR-H3 (SVYYFDY) as shown in SEQ ID NOs: 71, 75, and 78; and, CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRNT), and CDR-L3 (QQDYSSPYT) as shown in SEQ ID NOs: 45, 80, and 49;
(14) CDR-H1 (SYYIH), CDR-H2 (WIYPGNANNKYNENFKG), and CDR-H3 (SVYYFDY) as shown in SEQ ID NOs: 72, 76, and 78; and, CDR-L1 (KASQSVSNDVA), CDR-L2 (YASNRNT), and CDR-L3 (QQDYSSPYT) as shown in SEQ ID NOs: 45, 80, and 49;
(15) CDR-H1 (TSYYIH), CDR-H2 (WIGWIYPGNANNK), and CDR-H3 (ARSVYYFD) as shown in SEQ ID NOs: 73, 77, and 79; and, CDR-L1 (SNDVAWY), CDR-L2 (LLIYYASNRN), and CDR-L3 (QQDYSSPY) as shown in SEQ ID NOs: 46, 81, and 50;
(16) CDR-H1 (GYSFTDY), CDR-H2 (NPNNGN), and CDR-H3 (EDRYAFAY) as shown in SEQ ID NOs: 82, 86, and 90; and, CDR-L1 (RASQSVSTSSYTYMH), CDR-L2 (YASNLES), and CDR-L3 (QHTWEIPYT) as shown in SEQ ID NOs: 92, 94, and 96;
(17) CDR-H1 (GYSFTDYYMH), CDR-H2 (RVNPNNGNTL), and CDR-H3 (EDRYAFAY) as shown in SEQ ID NOs: 83, 87, and 90; and, CDR-L1 (RASQSVSTSSYTYMH), CDR-L2 (YASNLES), and CDR-L3 (QHTWEIPYT) as shown in SEQ ID NOs: 92, 94, and 96;
(18) CDR-H1 (DYYMH), CDR-H2 (RVNPNNGNTLYNQKFRG), and CDR-H3 (EDRYAFAY)as shown in SEQ ID NOs: 84, 88, and 90; and, CDR-L1 (RASQSVSTSSYTYMH), CDR-L2 (YASNLES), and CDR-L3 (QHTWEIPYT) as shown in SEQ ID NOs: 92, 94, and 96; and
(19) CDR-H1 (TDYYMH), CDR-H2 (WIGRVNPNNGNTL), and CDR-H3 (AREDRYAFA)as shown in SEQ ID NOs: 85, 89, and 91; and, CDR-L1 (STSSYTYMHWY), CDR-L2 (LLIKYASNLE), and CDR-L3 (QHTWEIPY) as shown in SEQ ID NOs: 93, 95, and 97.

### Claim 2 (depends on 1)

The antibody molecule or fragment thereof according to claim 1, wherein in the antibody molecule or fragment thereof, the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 7, 9, or 10, or an amino acid sequence having at least 75% identity to the amino acid sequence as shown; and, the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 8, 11, or 12, or an amino acid sequence having at least 75% identity to the amino acid sequence as shown; or,
the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 13, 15, 16, 18, 19, 20, or 21, or an amino acid sequence having at least 75% identity to the amino acid sequence as shown; and, the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 14, 22, 23, or 25, or an amino acid sequence having at least 75% identity to the amino acid sequence as shown; or
the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 27, 29, or 30, or an amino acid sequence having at least 75% identity to the amino acid sequence as shown; and, the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 28, 31, or 32, or an amino acid sequence having at least 75% identity to the amino acid sequence as shown; or
the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 33, or an amino acid sequence having at least 75% identity to the amino acid sequence as shown; and, the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 34, or an amino acid sequence having at least 75% identity to the amino acid sequence as shown.

### Claim 3 (depends on 1)

The antibody molecule or fragment thereof according to claim 1, wherein the heavy chain variable region and the light chain variable region in the antibody molecule or fragment thereof are selected from combinations of amino acid sequences as follows:
(1) an amino acid sequence as shown in SEQ ID NO: 7 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 7; and, an amino acid sequence as shown in SEQ ID NO: 8 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 8;
(2) an amino acid sequence as shown in SEQ ID NO: 9 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 9; and, an amino acid sequence as shown in SEQ ID NO: 11 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 11;
(3) an amino acid sequence as shown in SEQ ID NO: 9 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 9; and, an amino acid sequence as shown in SEQ ID NO: 12 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 12;
(4) an amino acid sequence as shown in SEQ ID NO: 10 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 10; and, an amino acid sequence as shown in SEQ ID NO: 11 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 11;
(5) an amino acid sequence as shown in SEQ ID NO: 10 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 10; and, an amino acid sequence as shown in SEQ ID NO: 12 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 12;
(6) an amino acid sequence as shown in SEQ ID NO: 13 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 13; and, an amino acid sequence as shown in SEQ ID NO: 14 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 14;
(7) an amino acid sequence as shown in SEQ ID NO: 16 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 16; and, an amino acid sequence as shown in SEQ ID NO: 22 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 22;
(8) an amino acid sequence as shown in SEQ ID NO: 16 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 16; and, an amino acid sequence as shown in SEQ ID NO: 23 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 23;
(9) an amino acid sequence as shown in SEQ ID NO: 16 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 16; and, an amino acid sequence as shown in SEQ ID NO: 25 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 25;
(10) an amino acid sequence as shown in SEQ ID NO: 19 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 19; and, an amino acid sequence as shown in SEQ ID NO: 25 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 25;
(11) an amino acid sequence as shown in SEQ ID NO: 21 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 21; and, an amino acid sequence as shown in SEQ ID NO: 25 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 25;
(12) an amino acid sequence as shown in SEQ ID NO: 27 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 27; and, an amino acid sequence as shown in SEQ ID NO: 28 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 28;
(13) an amino acid sequence as shown in SEQ ID NO: 29 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 29; and, an amino acid sequence as shown in SEQ ID NO: 32 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 32;
(14) an amino acid sequence as shown in SEQ ID NO: 30 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 30; and, an amino acid sequence as shown in SEQ ID NO: 32 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 32; or,
(15) an amino acid sequence as shown in SEQ ID NO: 33 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 33; and, an amino acid sequence as shown in SEQ ID NO: 34 or an amino acid sequence having at least 75% identity to the amino acid sequence as shown in SEQ ID NO: 34.

### Claim 4 (depends on 1)

The antibody molecule or fragment thereof according to claim 1, wherein the antibody molecule or fragment thereof binds to a poliovirus receptor-like molecule 4 (Nectin-4), preferably mammalian Nectin-4, more preferably primate Nectin-4, further preferably human or cyno Nectin-4, in particular human Nectin-4.

### Claim 5 (depends on 1)

The antibody molecule or fragment thereof according to claim 1, wherein the antibody molecule is a murine antibody, a chimeric antibody or a fully or partially humanized antibody; and, the fragment is single-chain variable fragment (scFv), disulfide-stabilized Fv fragment (dsFv), (disulfide-stabilized Fv fragment)2 (dsFv)2, Fab fragment, Fab′ fragment, F(ab′)2 fragment, or variable fragment (Fv) of the antibody molecule;
preferably, the antibody molecule is a monoclonal antibody or a single chain antibody;
preferably, the antibody molecule or fragment thereof further comprises a constant region,
preferably a murine or human heavy chain constant region (CH) and/or a light chain constant region (CL); preferably, the antibody molecule or fragment thereof comprises a heavy chain and a light chain;
more preferably, the antibody molecule or fragment thereof comprises a heavy chain constant region of an IgG, IgA, IgM, IgD, or IgE and/or a light chain constant region of a kappa or lambda type.

### Claim 6 (depends on 1)

The antibody molecule or fragment thereof according to claim 1, wherein the antibody molecule is a monoclonal antibody, preferably a humanized monoclonal antibody;
preferably, the heavy chain constant region of the monoclonal antibody is of an IgG1 type and the light chain constant region is of a kappa type.

### Claim 7 (depends on 1)

A nucleic acid molecule comprising a nucleotide sequence encoding a heavy chain variable region, a light chain variable region, a heavy chain or a light chain comprised in the antibody molecule or fragment thereof according to claim 1.

### Claim 8 (depends on 7)

A vector comprising the nucleic acid molecule according to claim 7.

### Claim 9 (depends on 8)

A host cell comprising the nucleic acid molecule and/or the vector according to claim 8, or transformed or transfected with the nucleic acid molecule and/or the vector.

### Claim 10 (depends on 9)

A composition comprising the antibody molecule or fragment thereof, the nucleic acid molecule, the vector, or the host cell according to claim 9;
preferably, the composition is a pharmaceutical composition, optionally comprising a pharmaceutically acceptable carrier, adjuvant, or excipient.

### Claim 11 (depends on 10)

Use of the antibody molecule or fragment thereof, the nucleic acid molecule, the vector, the host cell, or the composition according to claim 10 in the manufacture of an agent for the detection or diagnosis of a disease or disorder.

### Claim 12 (depends on 10)

A method for detecting or diagnosing a disease or disorder, comprising contacting the antibody molecule or fragment thereof, the nucleic acid molecule, the vector, the host cell, or the composition according to claim 10 with a sample from a subject;
wherein the subject is a mammal, preferably a primate, more preferably a human.

### Claim 13 (depends on 1)

Use of the antibody molecule or fragment thereof according to claim 1 in the preparation of an antibody-drug conjugate.

### Claim 14 (depends on 1)

An antibody-drug conjugate formed by conjugating an
antibody molecule or fragment thereof according to claim 1 to a cytotoxic moiety;
preferably, the cytotoxic moiety is a tubulin inhibitor, a topoisomerase inhibitor, or a DNA binding agent;
more preferably, the tubulin inhibitor is selected from the group consisting of Maytansinoids, Monomethyl auristatin E (MMAE), Monomethyl auristatin F (MMAF), Monomethyl Dolastatin 10, Tubulysin and its derivatives, Cryptophycin and its derivatives, and Taltobulin;
more preferably, the topoisomerase inhibitor is selected from the group consisting of PNU-159682, the metabolite of doxorubicin and its derivatives, and SN38, the metabolite of irinotecan (CPT-11) and its derivatives;
more preferably, the DNA binding agent is selected from the group consisting of PBD and its derivatives and Duocarmycine and its derivatives.

### Claim 15 (depends on 14)

Use of the antibody molecule or fragment thereof, the nucleic acid, the vector, the host cell, the composition, or the antibody-drug conjugate according to claim 14 in the manufacture of a medicament for the prevention or treatment of a disease or disorder.

### Claim 16 (depends on 14)

A method for preventing or treating a disease or disorder, comprising administering to a subject in need thereof the antibody molecule or fragment thereof, the nucleic acid molecule, the vector, the host cell, the composition, or the antibody-drug conjugate according to claim 14;
wherein the subject is a mammal, preferably a primate, more preferably a human.

### Claim 17 (depends on 14)

A kit comprising the antibody molecule or fragment thereof, the nucleic acid molecule, the vector, the host cell, the composition, or the antibody-drug conjugate according to claim 14;
preferably, the kit is used for treating, detecting or diagnosing a disease or disorder.

### Claim 18 (depends on 11)

The use, the method, or the kit according to claim 11, wherein the disease or disorder is a tumor or cancer in which Nectin-4 is highly expressed;
preferably, the disease or disorder is a solid tumor;
preferably, the disease or disorder is bladder cancer, pancreatic cancer, breast cancer (including triple negative and basal subtypes), non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, etc.; in particular bladder, breast, ovarian or lung cancer.