# US 2019/0315873 A1 · Anti-met antibodies and uses thereof

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- Number: US 2019/0315873 A1
- Document ID: US20190315873A1
- Status: Published application
- Kind: A1
- Application number: 16/313,710
- Filed: 2017-06-23
- Published: 2019-10-17
- Earliest claimed: 2016-06-27
- Assignees: Agomab Therapeutics Bvba
- Applicants: Agomab Therapeutics Bvba
- Inventors: Paolo MICHIELI
- Web page: https://patentgrep.com/patent/US20190315873A1

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- 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 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/22: from camelids, e.g. camel, llama or dromedary
- 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 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/522: CH1 domain
- C07K 2317/524: CH2 domain
- C07K 2317/526: CH3 domain
- C07K 2317/528: CH4 domain
- C07K 2317/53: Hinge
- C07K 2317/55: Fab or Fab'
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/74: Inducing cell proliferation
- 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
- 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)

## Abstract

The invention relates to agonistic anti-MET antibodies and uses thereof in the therapeutic treatment of disease. The antibodies bind with high affinity to the human and mouse hepatocyte growth factor (HGF) receptor, also known as MET, and are agonists of MET in both humans and mice, producing molecular and cellular effects resembling the effects of HGF binding.

## Claims

### Claim at position 1

1-60. (canceled)

### Claim 61

An antibody, or an antigen binding fragment thereof, which binds human MET protein (hMET) with high affinity and binds mouse MET protein (mMET) with high affinity, wherein the antibody or an antigen binding fragment thereof is a hMET agonist and a mMET agonist.

### Claim 62 (depends on 61)

The antibody or antigen binding fragment thereof of claim 61, wherein the antibody or antigen binding fragment thereof meets one or more of the following conditions:
it comprises at least one heavy chain variable domain (VH) and at least one light chain variable domain (VL), wherein said VH and VL domain, when tested as a Fab fragment, exhibit an off-rate (koff measured by Biacore) for hMET in the range of from 1×10−3 s−1 to 1×10−2 s−1, optionally 1×10−3 s−1 to 6×10−3 s−1, and exhibit an off-rate (koff measured by Biacore) for mMET in the range of from 1×10−3 s−1 to 1×10−2 s−1, optionally 1×10−3 s−1 to 6×10−3 s−1;
it has equivalent affinity for hMET and mMET;
it induces phosphorylation of hMET and induces phosphorylation of mMET;
it induces phosphorylation of hMET with an EC50 (as measured by phospho-MET ELISA) of less than 3.0 nM, optionally less than 2.0 nM and induces phosphorylation of mMET with an EC50 (as measured by phospho-MET ELISA) of less than 3.0 nM, optionally less than 2.0 nM;
it induces phosphorylation of hMET and mMET equivalently;
it exhibits high phosphorylation potency for hMET and exhibits high phosphorylation potency for mMET;
it induces phosphorylation of hMET with an EC50 of less than 1 nM and/or an Emax (as a percentage of HGF-induced activation in a phospho-MET ELISA) of at least 80% and induces phosphorylation of mMET with an EC50 of less than 1 nM and/or an Emax (as a percentage of HGF-induced activation in a phospho-MET ELISA) of at least 80%;
it exhibits low phosphorylation potency for hMET and exhibits low phosphorylation potency for mMET; and
it induces phosphorylation of hMET with EC50 of 1 nM-5 nM and/or an Emax (as a percentage of HGF-induced activation in a phospho-MET ELISA) of 60-80% and induces phosphorylation of mMET with EC50 of 1 nM-5 nM and/or an Emax (as a percentage of HGF-induced activation in a phospho-MET ELISA) of 60-80%.

### Claim 63 (depends on 61)

The antibody or antigen binding fragment thereof of claim 61, wherein the antibody or antigen binding fragment thereof induces an HGF-like cellular response when contacted with a human cell and induces an HGF-like cellular response when contacted with a mouse cell.

### Claim 64 (depends on 63)

The antibody or antigen binding fragment thereof of claim 63, wherein the antibody or antigen binding fragment thereof fully induces an HGF-like cellular response when contacted with a human cell and when contacted with a mouse cell, or partially induces an HGF-like cellular response when contacted with a human cell and when contacted with a mouse cell.

### Claim 65 (depends on 64)

The antibody or antigen binding fragment thereof of claim 64, wherein:
full induction of HGF-like cellular response is measurable as one, any two, or all of:
(i) in a cell scattering assay, the antibody or antigen binding fragment thereof induces cell scattering comparable to maximal HGF-induced scattering when the antibody or antigen binding fragment thereof is at a concentration of 0.1-1.0 nM;
(ii) in an anti-apoptotic cell assay, the antibody or antigen binding fragment thereof exhibits an EC50 of less than 1.1× that of HGF, and/or with an Emax (measured as a of total ATP content of non-apoptotic control cells) of greater than 90% that observed for HGF; and/or
(iii) in a branching morphogenesis assay, cells treated with the antibody exhibit greater than 90% of the number of branches per spheroid induced by the same (non-zero) concentration of HGF; and
partial induction of an HGF-like cellular response is measurable as:
(i) in a cell scattering assay, the antibody or antigen binding fragment thereof induces cell scattering of at least 25% that induced by 0.1 nM homologous HGF when the antibody concentration is 1 nM or lower;
(ii) in anti-apoptotic cell assay, the antibody or antigen binding fragment thereof exhibits an EC50 no more than 7.0× that of HGF and/or an Emax cellular viability of at least 50% that observed for HGF; and/or
(iii) in a branching morphogenesis assay, cells treated with the antibody exhibit at least 25% the number of branches per spheroid induced by the same (non-zero) concentration of HGF; and
and the antibody or antigen binding fragment does not fully induce an HGF-like cellular response.

### Claim 66 (depends on 61)

The antibody or antigen binding fragment thereof of claim 61, wherein the antibody or antigen binding fragment thereof is a HGF competitor.

### Claim 67 (depends on 66)

The antibody or antigen binding fragment thereof of claim 66, wherein the antibody or antigen binding fragment thereof meets one or more of the following conditions:
it competes with hHGF binding to hMET with an IC50 of no more than 5 nM and/or an Imax of at least 50% and competes with mHGF binding to mMET with an IC50 of no more than 5 nM and/or an Imax of at least 50%;
it competes with hHGF and mHGF equivalently;
it is a full HGF competitor;
it is a full HGF competitor which competes with hHGF with an IC50 of less than 2 nM and/or an Imax of greater than 90% and competes with mHGF with an IC50 of less than 2 nM and/or an Imax of greater than 90%;
it is a partial HGF competitor; and
it is a partial HGF competitor which competes with hHGF with an IC50 of 2-5 nM and/or an Imax of 50%-90% and competes with mHGF with an IC50 of 2-5 nM and/or an Imax of 50%-90%.

### Claim 68

An antibody or antigen binding fragment thereof which recognizes an epitope of human MET located in a region from amino acid residue 123 to residue 223 of human MET, from amino acid residue 224 to residue 311 of human MET, from residue 314 to residue 372 of human MET or from residue 546 to residue 562 of human MET.

### Claim 69 (depends on 68)

The antibody or antigen binding fragment thereof of claim 68 which:
recognizes an epitope in the extracellular domain of MET that comprises one or more amino acids conserved across human and mouse MET;
recognizes an epitope of human MET comprising the amino acid residue Ile367 and/or Asp372 of human MET, optionally wherein the epitope is located in the region from amino acid residue 314 to residue 372 of human MET; or
recognizes an epitope of human MET comprising the amino acid residue Thr555 of human MET optionally wherein the epitope is located in the region from amino acid residue 546 to residue 562 of human MET.

### Claim 70 (depends on 68)

The antibody according to claim 68, which binds human MET protein (hMET) with high affinity and binds mouse MET protein (mMET) with high affinity, wherein the antibody or an antigen binding fragment thereof is a hMET agonist and a mMET agonist.

### Claim 71

An antibody or antigen binding fragment which comprises a heavy chain variable domain comprising H-CDR1, H-CDR2 and H-CDR3, and a light chain variable domain comprising L-CDR1, L-CDR2 and L-CDR3, wherein:
H-CDR1 comprises the amino acid sequence shown as SEQ ID NO:44,
H-CDR2 comprises the amino acid sequence shown as SEQ ID NO:46,
H-CDR3 comprises the amino acid sequence shown as SEQ ID NO:48,
L-CDR1 comprises the amino acid sequence shown as SEQ ID NO:121,
L-CDR2 comprises the amino acid sequence shown as SEQ ID NO:123, and
L-CDR3 comprises the amino acid sequence shown as SEQ ID NO:125.

### Claim 72 (depends on 71)

The antibody or antigen binding fragment according to claim 71, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:167, or a sequence at least 90%, 95%, 97% or 99% identical thereto, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:168, or a sequence at least 90%, 95%, 97% or 99% identical thereto, or which binds human MET protein (hMET) with high affinity and binds mouse MET protein (mMET) with high affinity, wherein the antibody or an antigen binding fragment thereof is a hMET agonist and a mMET agonist.

### Claim 73

An antibody or antigen binding fragment which comprises a heavy chain variable domain comprising H-CDR1, H-CDR2 and H-CDR3, and a light chain variable domain comprising L-CDR1, L-CDR2 and L-CDR3, wherein:
H-CDR1 comprises the amino acid sequence shown as SEQ ID NO:30,
H-CDR2 comprises the amino acid sequence shown as SEQ ID NO:32,
H-CDR3 comprises the amino acid sequence shown as SEQ ID NO:34,
L-CDR1 comprises the amino acid sequence shown as SEQ ID NO:107,
L-CDR2 comprises the amino acid sequence shown as SEQ ID NO:109, and
L-CDR3 comprises the amino acid sequence shown as SEQ ID NO:111.

### Claim 74 (depends on 73)

The antibody or antigen binding fragment according to claim 73, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:163, or a sequence at least 90%, 95%, 97% or 99% identical thereto, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:164, or a sequence at least 90%, 95%, 97% or 99% identical thereto, or which binds human MET protein (hMET) with high affinity and binds mouse MET protein (mMET) with high affinity, wherein the antibody or an antigen binding fragment thereof is a hMET agonist and a mMET agonist.

### Claim 75

An antibody or antigen binding fragment which comprises a heavy chain variable domain comprising H-CDR1, H-CDR2 and H-CDR3, and a light chain variable domain comprising L-CDR1, L-CDR2 and L-CDR3, wherein:
H-CDR1 comprises the amino acid sequence shown as SEQ ID NO:9,
H-CDR2 comprises the amino acid sequence shown as SEQ ID NO:11,
H-CDR3 comprises the amino acid sequence shown as SEQ ID NO:13,
L-CDR1 comprises the amino acid sequence shown as SEQ ID NO:86,
L-CDR2 comprises the amino acid sequence shown as SEQ ID NO:88, and
L-CDR3 comprises the amino acid sequence shown as SEQ ID NO:90.

### Claim 76 (depends on 75)

The antibody or antigen binding fragment according to claim 75, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:157, or a sequence at least 90%, 95%, 97% or 99% identical thereto, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:158, or a sequence at least 90%, 95%, 97% or 99% identical thereto, or which binds human MET protein (hMET) with high affinity and binds mouse MET protein (mMET) with high affinity, wherein the antibody or an antigen binding fragment thereof is a hMET agonist and a mMET agonist.

### Claim 77 (depends on 61)

An affinity variant or human germlined variant of an antibody or antigen binding fragment according to claim 61.

### Claim 78 (depends on 61)

The antibody or antigen binding fragment of claim 61 which meets one of more of the following conditions:
it contains the hinge region, CH2 domain and/or CH3 domain of a human IgG, optionally IgG1;
it has a sequence at least 90%, 95%, 97% or 99% identical to a human IgG, preferably IgG1, optionally wherein the CH2 and/or CH3 domain has been modified in order to reduce or substantially eliminate one or more antibody effector functions; and
its VH and/or VL domains or one or more of the CDRs are derived from an animal of the Camelidae family; —its VH and/or VL domains or one or more of the CDRs are derived from an animal of the Camelidae family wherein the animal is a llama.

### Claim 79 (depends on 61)

An isolated polynucleotide which encodes the antibody or antigen binding fragment of claim 61.

### Claim 80 (depends on 79)

An expression vector comprising the polynucleotide of claim 79 operably linked to regulatory sequences which permit expression of the antibody or antigen binding fragment thereof in a host cell or cell-free expression system.

### Claim 81 (depends on 80)

A host cell or cell-free expression system containing the expression vector of claim 80.

### Claim 82 (depends on 81)

A method of producing a recombinant antibody or antigen binding fragment thereof which comprises culturing the host cell or cell free expression system of claim 81 under conditions which permit expression of the antibody or antigen binding fragment and recovering the expressed antibody or antigen binding fragment.

### Claim 83 (depends on 61)

A pharmaceutical composition comprising an antibody or antigen binding fragment according to claim 61 and at least one pharmaceutically acceptable carrier or excipient.

### Claim 84 (depends on 61)

A method of treating or preventing a disease, comprising administering to a patient in need thereof a therapeutically effective amount of an antibody or antigen binding fragment according to claim 61.

### Claim 85 (depends on 83)

A method of treating or preventing a disease, comprising administering to a patient in need thereof a therapeutically effective amount the pharmaceutical composition of claim 83.

### Claim 86 (depends on 84)

The method according to claim 84, wherein said disease is:
liver damage in a human patient, optionally acute liver damage or chronic liver damage;
kidney damage in a human patient, optionally acute kidney damage;
inflammatory bowel disease in a human patient, optionally ulcerative colitis;
diabetes in a human patient, optionally type I or type II diabetes;
non-alcoholic steatohepatitis in a human patient; or
wound healing in a human patient, optionally a patient having diabetes.

### Claim 87 (depends on 85)

The method according to claim 85, wherein said disease is:
liver damage in a human patient, optionally acute liver damage or chronic liver damage;
kidney damage in a human patient, optionally acute kidney damage;
inflammatory bowel disease in a human patient, optionally ulcerative colitis;
diabetes in a human patient, optionally type I or type II diabetes;
non-alcoholic steatohepatitis in a human patient; or
wound healing in a human patient, optionally a patient having diabetes.