# US 12,180,287 B2 · Anti-c-Met antibody showing enhanced stability or antigen-binding fragments thereof

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- Number: US 12,180,287 B2
- Document ID: US12180287B2
- Status: Granted
- Kind: B2
- Application number: 17/293,703
- Filed: 2019-11-13
- Published: 2021-12-30
- Granted: 2024-12-31
- Earliest claimed: 2018-11-14
- Assignees: Helixmith Co., Ltd
- Applicants: Helixmith Co., Ltd
- Inventors: Jae-Gyun Jeong; Junghun Lee; Sang Ho Kwon
- Web page: https://patentgrep.com/patent/US12180287B2

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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 2317/70: characterized by effect upon binding to a cell or to an antigen
- C07K 2317/75: Agonist effect on antigen
- 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
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to an anti-c-Met antibody showing enhanced stability or antigen-binding fragments thereof, and the use thereof. Compared to 1E4 which is a parent antibody, the anti-c-Met antibody showing enhanced stability or antigen-binding reduced immunogenicity. Therefore, the anti-c-Met antibody or antigen-binding fragments thereof according to the present invention exhibits, in anti-c-Met antibody development, excellent properties such as reduced production cost, inhibition of reduced efficacy, reduced side effects and the like.

## Claims

### Claim 1

An anti-c-Met antibody or an antigen-binding fragment comprising:
(a) an immunoglobulin heavy chain variable domain comprising the structure of FRH1-CDRH1-FRH2-CDRH2-FRH3-CDRH3-FRH4; and
(b) an immunoglobulin light chain variable domain comprising the structure of FRL1-CDRL1-FRL2-CDRL2-FRL3-CDRL3-FRL4:
wherein the CDRH1, the CDRH2, and the CDRH3 comprise the amino acid sequences of SEQ ID NOS: 1, 2, and 3, respectively, and the CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences of SEQ ID NOS: 4, 5, and 6, respectively,
wherein (a) and (b) are selected from the following group:
i) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 11 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;
ii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 12 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;
iii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 12 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;
iv) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;
v) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18
vi) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 21;
vii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 15 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;
viii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 15 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;
ix) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17; and
x) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18.

### Claim 2 (depends on 1)

The anti-c-Met antibody or antigen-binding fragment of claim 1, comprising
i) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 34 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42;
ii) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 35 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 41;
iii) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 35 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42;
iv) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 37 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 41;
v) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 37 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42;
vi) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 37 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 45;
vii) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 38 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 41;
viii) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 38 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42;
ix) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 39 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 41 and
x) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 39 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42.

### Claim 3 (depends on 1)

The anti-c-Met antibody or antigen-binding fragment of claim 1, wherein the antigen-binding fragment is Fab, Fab′, F(ab′)2, Fv, scFv or chemically linked F(ab′)2.

### Claim 4

An anti-c-Met antibody or antigen-binding fragment, comprising:
(a) a heavy chain variable domain comprising CDRH1 (complementarity determining region 1 of heavy chain) of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, and CDRH3 of SEQ ID NO: 3;
(b) an immunoglobulin heavy chain constant domain comprising CH1 (constant domain 1 of heavy chain) of SEQ ID NO: 7;
(c) an immunoglobulin light chain variable domain comprising CDRL1 (complementarity determining region 1 of light chain) of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6; and
(d) an immunoglobulin light chain constant domain comprising Ck (kappa-constant domain) of SEQ ID NO: 8,
wherein at least one of the amino acid residue at position 97 in CH1 of SEQ ID NO: 7 and the amino acid residue at position 2 in Ck of SEQ ID NO: 8 is mutated by substitution with arginine or threonine,
wherein (a) and (b) are selected from the following group:
i) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 11 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;
ii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 12 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;
iii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 12 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;
iv) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;
v) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18 vi) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 21;
vii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 15 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;
viii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 15 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;
ix) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17; and
x) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18.

### Claim 5 (depends on 4)

The anti-c-Met antibody or antigen-binding fragment of claim 4, wherein the amino acid residue at position 97 in CH1 of SEQ ID NO: 7 and the amino acid residue at position 2 in Ck of SEQ ID NO: 8 are mutated by substitution with arginine and threonine, respectively.