# US 11,299,542 B2 · Monoclonal antibodies to progastrin and their uses

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- Number: US 11,299,542 B2
- Document ID: US11299542B2
- Status: Granted
- Kind: B2
- Application number: 16/456,328
- Filed: 2019-06-28
- Published: 2020-01-02
- Granted: 2022-04-12
- Earliest claimed: 2009-10-16
- Assignees: Les Laboratories Servier; Institut National de Santé et de la Recherche Médicale (INSERM); Centre National de la Recherche Scientifiaue (CNRS)
- Applicants: Les Laboratoires Servier; Institut National de la Santé et de la Recherche Médicale (INSERM); Centre National de la Recherche Scientifique (CNRS)
- Inventors: Julie Pannequin; Laure Boudier; Dominique Joubert; Frédéric Hollande
- Web page: https://patentgrep.com/patent/US11299542B2

## CPC

- C07K 16/26: against hormones {; against hormone releasing or inhibiting factors}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 35/00: Antineoplastic agents
- G01N 33/57535: of the large intestine, e.g. colon, rectum or anus
- G01N 33/57585: {involving compounds identifiable in body fluids}
- 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 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/567: Framework region [FR]
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- G01N 2333/595: Gastrins; Cholecystokinins [CCK]
- 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
- 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)
- 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 present disclosure is directed to progastrin monoclonal antibodies, fragments thereof, compositions comprising progastrin monoclonal antibodies, and methods of making and using progastrin monoclonal antibodies and compositions thereof. The present disclosure is directed to methods of treating colorectal cancer with progastrin monoclonal antibodies and compositions comprising progastrin monoclonal antibodies or fragments thereof. The present disclosure is further directed to methods comprising detection of progastrin, including methods of diagnosing colorectal cancer and methods of monitoring efficacy of anti-cancer therapy in subjects suffering from colorectal cancer.

## Claims

### Claim 1

A monoclonal antibody that specifically binds a human progastrin (hPG) polypeptide having an amino acid sequence of SEQ ID NO:20, but does not detectably bind to an amidated gastrin 17 consisting of SEQ ID NO:103, a glycine-extended gastrin 17 consisting of SEQ ID NO:104, or C-terminal Flanking Peptide (CTFP) consisting of SEQ ID NO:105, wherein said monoclonal antibody is a N-terminal anti-hPG monoclonal antibody that specifically binds a N-terminal region of hPG, wherein:
(a) the antibody is obtainable using an immunogen comprising a peptide antigen having an amino acid sequence of SEQ ID NO:25; and
(b) the antibody comprises VH CDRs comprising amino acid sequences of VH CDR 1.4 (SEQ ID NO:7), VH CDR 2.4 (SEQ ID NO:8), VH CDR 3.4 (SEQ ID NO:9) and VL CDRs comprising amino acid sequences of VL CDR 1.4 (SEQ ID NO:10), VL CDR 2.4 (SEQ ID NO:5), and VL CDR 3.4 (SEQ ID NO:11).

### Claim 2

A monoclonal antibody that specifically binds a human progastrin (hPG) polypeptide having an amino acid sequence of SEQ ID NO:20, but does not detectably bind to an amidated gastrin 17 consisting of SEQ ID NO:103, a glycine-extended gastrin 17 consisting of SEQ ID NO:104, or C-terminal Flanking Peptide (CTFP) consisting of SEQ ID NO:105, wherein said monoclonal antibody is a N-terminal anti-hPG monoclonal antibody that specifically binds a N-terminal region of hPG, wherein:
(a) the antibody is obtainable using an immunogen comprising a peptide antigen having an amino acid sequence of SEQ ID NO:25; and
(b) the antibody comprises V1 and VH CDRs having the amino acid sequences of the VL and VH CDRs of an antibody comprising a VH of SEQ ID NO:14 and a VL of SEQ ID NO:15.

### Claim 3

A monoclonal antibody that specifically binds a human progastrin (hPG) polypeptide having an amino acid sequence of SEQ ID NO:20, but does not detectably bind to an amidated gastrin 17 consisting of SEQ ID NO:103, a glycine-extended gastrin 17 consisting of SEQ ID NO:104, or C-terminal Flanking Peptide (CTFP) consisting of SEQ ID NO:105, wherein said monoclonal antibody is a N-terminal anti-hPG monoclonal antibody that specifically binds a N-terminal region of hPG, wherein:
(a) the antibody is obtainable using an immunogen comprising a peptide antigen having an amino acid sequence of SEQ ID NO:25; and
(b) the antibody comprises VH and VL chains having amino acid sequences of hVH 3 (SEQ ID NO:23) and hVL 3 (SEQ ID NO:24).

### Claim 4

A monoclonal antibody that specifically binds a human progastrin polypeptide and comprises a VH chain comprising CDRs having the amino acid sequence of VH CDR 1.4 (SEQ ID NO:7), VH CDR 2.4 (SEQ ID NO:8), VH CDR 3.4 (SEQ ID NO:9) and VL CDRs comprising amino acid sequences of VL CDR 1.4 (SEQ ID NO:10), VL CDR 2.4 (SEQ ID NO:5), and VL CDR 3.4 (SEQ ID NO:11).

### Claim 5 (depends on 4)

The monoclonal antibody of claim 4, which is humanized.

### Claim 6 (depends on 5)

The monoclonal antibody of claim 5, which comprises VH and VL chains having amino acid sequences of hVH 3 (SEQ ID NO:23) and hVL 3 (SEQ ID NO:24).

### Claim 7 (depends on 4)

The monoclonal antibody of claim 4, which reduces the binding of a reference antibody to hPG by at least 40% when said monoclonal antibody and the reference antibody are each used at a concentration of 10 pg/ml.

### Claim 8 (depends on 5)

The monoclonal antibody of claim 5, which neutralizes hPG activity in an in vitro assay.

### Claim 9 (depends on 4)

A composition comprising a monoclonal antibody according to claim 4 and an excipient, carrier, and/or diluent.

### Claim 10 (depends on 9)

The composition of claim 9, which is formulated for pharmaceutical use.

### Claim 11 (depends on 4)

A polynucleotide encoding a variable light chain for a monoclonal antibody according to claim 4.

### Claim 12 (depends on 4)

A polynucleotide encoding a variable heavy chain for a monoclonal antibody according to claim 4.

### Claim 13 (depends on 4)

An expression vector comprising a polynucleotide encoding a variable light chain for a monoclonal antibody according to claim 4.

### Claim 14 (depends on 4)

An expression vector comprising a polynucleotide encoding a variable heavy chain for a monoclonal antibody according to claim 4.

### Claim 15 (depends on 4)

A cell line transformed with pairs of polynucleotides suitable for expressing a monoclonal antibody according to claim 4.

### Claim 16 (depends on 4)

A cell line capable of secreting an anti-hPG monoclonal antibody according to claim 4.

### Claim 17 (depends on 15)

A method of obtaining a monoclonal antibody that specifically binds a human progastrin polypeptide and comprises a VH chain comprising CDRs having the amino acid sequence of VH CDR 1.4 (SEQ ID NO:7), VH CDR 2.4 (SEQ ID NO:8), VH CDR 3.4 (SEQ ID NO:9) and VL CDRs comprising amino acid sequences of VL CDR 1.4 (SEQ 9D NO:10), VL CDR 2.4 (SEQ ID NO:5), and VL CDR 3.4 (SEQ ID NO:11) comprising:
(a) culturing a cell line of claim 15 under suitable conditions; and
(b) recovering said monoclonal antibody from the culture medium or cells of the cell line.

### Claim 18 (depends on 4)

A kit useful for detecting human progastrin polypeptide (hPG), comprising a monoclonal antibody according to claim 4 and an antibody that specifically binds a C-terminal region of hPG.

### Claim 19 (depends on 18)

The kit of claim 18, wherein the antibody that specifically binds a C-terminal region of hPG is a polyclonal antibody.

### Claim 20

A cell line which recombinantly expresses an anti-human progastrin antibody comprising a VH of SEQ ID NO:14 and a VL of SEQ ID NO:15.