# US 2010/0169992 A1 · Fgfr4 antibodies

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- Number: US 2010/0169992 A1
- Document ID: US20100169992A1
- Status: Published application
- Kind: A1
- Application number: 12/513,448
- Filed: 2007-11-02
- Published: 2010-07-01
- Earliest claimed: 2006-11-03
- Assignees: U3 Pharma GmbH
- Inventors: Johannes Bange; Jens Niewoehner; Patricia Aus Dem Siepen; Mike Rothe
- Web page: https://patentgrep.com/patent/US20100169992A1

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- G01N 33/6854: {Immunoglobulins}
- 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
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)

## Abstract

The present invention relates to FGFR4 antibodies including fragments or derivatives thereof and the polynucleotides encoding the antibodies. Expression vectors and host cells comprising the polynucleotides are provided. Further, the invention refers to pharmaceutical compositions comprising the FGFR4 antibodies and methods for the treatment, prevention or diagnosis of disorders associated with FGFR4 expression.

## Claims

### Claim at position 1

1-40. (canceled)

### Claim 41

An antibody that binds to the extracellular domain of FGFR4 and at least partially inhibits FGFR4 activity, wherein the antibody reduces or blocks FGFR4 phosphorylation.

### Claim 42 (depends on 41)

The antibody of claim 41 which comprises:
at least one heavy chain amino acid sequence comprising at least one CDR selected from the group consisting of
(a) a CDRH1 as shown in SEQ ID NOs: 9 or 15, or a CDRH1 sequence differing in 1 or 2 amino acids therefrom,
(b) a CDRH2 as shown in SEQ ID NOs: 10 or 16, or a CDRH2 sequence differing in 1 or 2 amino acids therefrom, and
(c) a CDRH3 as shown in SEQ ID NOs: 11 or 17, or a CDRH3 sequence differing in 1 or 2 amino acids therefrom, and/or
at least one light chain amino acid sequence comprising at least one CDR selected from the group consisting of:
(d) a CDRL1 as shown in SEQ ID NOs: 12 or 18, or a CDRL1 sequence differing in 1 or 2 amino acids therefrom,
(e) a CDRL2 as shown in SEQ ID NOs: 13 or 19, or a CDRL2 sequence differing in 1 or 2 amino acids therefrom, and
(f) a CDRL3 as shown in SEQ ID NOs: 14 or 20, or a CDRL3 sequence differing in 1 or 2 amino acids therefrom,
or an antibody recognizing the same epitope on the extracellular domain of FGFR4.

### Claim 43 (depends on 41)

The antibody of claim 41 which comprises a heavy chain comprising at least one CDR selected from the group consisting of
(a) a CDRH1 as shown in SEQ ID NO: 9, or a CDRH1 sequence differing in 1 or 2 amino acids therefrom,
(b) a CDRH2 as shown in SEQ ID NO: 10, or a CDRH2 sequence differing in 1 or 2 amino acids therefrom, and
(c) a CDRH3 as shown in SEQ ID NO: 11, or a CDRH3 sequence differing in 1 or 2 amino acids therefrom, and/or
a light chain comprising at least one CDR selected from the group consisting of
(d) a CDRL1 as shown in SEQ ID NO: 12, or a CDRL1 sequence differing in 1 or 2 amino acids therefrom,
(e) a CDRL2 as shown in SEQ ID NO: 13 or a CDRL2 sequence differing in one or two amino acids therefrom, and
(f) a CDRL3 as shown in SEQ ID NO: 14, or a CDRL3 sequence differing in 1 or 2 amino acids therefrom, or an antibody recognizing the same epitope on the extracellular domain of FGFR4.

### Claim 44 (depends on 41)

The antibody of claim 41, which comprises a heavy chain comprising at at least one CDR selected from the group consisting of
(a) a CDRH1 as shown in SEQ ID NO: 15, or a CDRH1 sequence differing in 1 or 2 amino acids therefrom,
(b) a CDRH2 as shown in SEQ ID NO: 16, or a CDRH2 sequence differing in 1 or 2 amino acids therefrom, and
(c) a CDRH3 as shown in SEQ ID NO: 17, or a CDRH3 sequence differing in 1 or 2 amino acids therefrom, and/or
a light chain comprising at least one CDR selected from the group consisting of
(d) a CDRL1 as shown in SEQ ID NO: 18, or a CDRL1 sequence differing in 1 or 2 amino acids therefrom,
(e) a CDRL2 as shown in SEQ ID NO: 19, or a CDRL2 sequence differing in 1 or 2 amino acids therefrom, and
(f) a CDRL3 as shown in SEQ ID NO: 20, or a CDRL3 sequence differing in 1 or 2 amino acids therefrom, or
an antibody recognizing the same epitope on the extracellular domain of FGFR4.

### Claim 45 (depends on 41)

The antibody of claim 41, which comprises a heavy chain amino acid sequence selected from the group consisting of SEQ ID NOs: 5 and 7 or at least the variable domain thereof or an amino acid sequence having an identity of at least 90% thereto and/or a light chain amino acid sequence selected from the group consisting of SEQ ID NOs: 6 and 8 or at least the variable domain thereof or an amino acid sequence having an identity of at least 90% thereto or an antibody recognizing the same epitope on the extracellular domain of FGFR4.

### Claim 46 (depends on 41)

The antibody according to claim 41, which reduces or blocks FGFR4-mediated signal transduction.

### Claim 47 (depends on 41)

The antibody according to claim 41, which reduces or blocks ligand binding.

### Claim 48 (depends on 41)

The antibody according to claim 41, which reduces or blocks cell proliferation.

### Claim 49 (depends on 41)

The antibody according to claim 41, which reduces or blocks cell migration.

### Claim 50 (depends on 41)

The antibody according to claim 41, which is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or a fragment thereof.

### Claim 51 (depends on 41)

The antibody according to claim 41, which is a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fv fragment, a diabody, or a single chain antibody molecule.

### Claim 52 (depends on 41)

The antibody according to claim 41, which is of the IgG1-, IgG2-, IgG3- or IgG4-type.

### Claim 53 (depends on 41)

The antibody according to claim 41, which is coupled to a labelling group.

### Claim 54 (depends on 53)

The antibody according to claim 53, wherein the labelling group is a radioisotope or radionuclide, a fluorescent group, an enzymatic group, a chemiluminescent group, a biotinyl group, or a predetermined polypeptide epitope.

### Claim 55 (depends on 41)

The antibody according to claim 41, which is coupled to an effector group.

### Claim 56 (depends on 55)

The antibody according to claim 55, wherein the effector group is a radioisotope or radionuclide, a toxin, or a therapeutic or chemotherapeutic group.

### Claim 57 (depends on 56)

The antibody according to claim 56, wherein the therapeutic or chemotherapeutic group is selected from the group consisting of calicheamicin, Auristatin-PE, geldanamycin and maytansin derivatives.

### Claim 58 (depends on 41)

The antibody according to claim 41, which is a scaffold protein.

### Claim 59 (depends on 41)

An isolated nucleic acid molecule selected from the group consisting of:
(a) a nucleic acid sequence encoding an antibody, antibody fragment or derivative thereof of claim 41,
(b) a nucleic acid sequence as shown in SEQ ID NOs: 1-4,
(c) a nucleic acid complementary to any of the sequences in (a) or (b); and
(d) a nucleic acid sequence capable of hybridizing to (a), (b) or (c) under stringent conditions.

### Claim 60 (depends on 59)

A vector comprising a nucleic acid sequence of claim 59.

### Claim 61 (depends on 69)

The vector according to claim 69, which is an expression vector and the nucleic acid sequence is operably linked to a control sequence.

### Claim 62 (depends on 60)

A host comprising the vector of claim 60.

### Claim 63 (depends on 62)

The host of claim 62 which is a human, bacteria, animal, fungal, amphibian or plant cell.

### Claim 64 (depends on 62)

The host of claim 62 which is a non-human transgenic animal.

### Claim 65 (depends on 62)

A process of manufacturing an antibody that binds to the extracellular domain of FGFR4 and at least partially inhibits FGFR4 activity, wherein the antibody reduces or blocks FGFR4 phosphorylation, comprising the step of obtaining said polypeptide from the host of claim 62.

### Claim 66

A pharmaceutical composition comprising an antibody that binds to the extracellular domain of FGFR4 and at least partially inhibits FGFR4 activity, wherein the antibody reduces or blocks FGFR4 phosphorylation.

### Claim 67 (depends on 66)

The pharmaceutical composition of claim 66 comprising pharmaceutically acceptable carriers, diluents and/or adjuvants.

### Claim 68 (depends on 66)

The pharmaceutical composition according to claim 66, optionally comprising a further active agent.

### Claim 69 (depends on 66)

The pharmaceutical composition according to claim 66, for the diagnosis, prevention or treatment of a hyperproliferative disease.

### Claim 70 (depends on 69)

The pharmaceutical composition according to claim 69, wherein said hyperproliferative disease is associated with FGFR4 expression, overexpression and/or hyperactivity.

### Claim 71 (depends on 69)

The pharmaceutical composition of claim 69, wherein said hyperproliferative disease is selected from the group consisting of breast cancer, gastrointestinal cancer, pancreas cancer, prostate cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary gland cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, thyroid cancer, bladder cancer, glioma, melanoma, other FGFR4 expressing or overexpressing cancers, and formation of tumor metastases.

### Claim 72 (depends on 41)

Use of the antibody according to claim 41 for the manufacture of a pharmaceutical composition for the diagnosis, prevention or treatment of a hyperproliferative disease.

### Claim 73 (depends on 72)

The use according to claim 72, wherein said hyperproliferative disease is selected from the group consisting of breast cancer, gastrointestinal cancer, pancreas cancer, prostate cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary gland cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, thyroid cancer, bladder cancer, glioma, melanoma, other FGFR4 expressing or overexpressing cancers, and formation of tumor metastases.

### Claim 74 (depends on 41)

A method for diagnosing a condition associated with the expression of FGFR4, comprising contacting a sample with an antibody according to claim 41, and detecting the presence of FGFR4.

### Claim 75 (depends on 74)

The method according to claim 74, wherein the condition is a hyperproliferative disease associated with FGFR4 expression, overexpression and/or hyperactivity.

### Claim 76 (depends on 41)

A method for preventing or treating a condition associated with the expression of FGFR4 in a patient, comprising administering to a patient in need thereof an effective amount of at least the antibody according to claim 41.

### Claim 77 (depends on 75)

The method according to claim 75, wherein the condition is a hyperproliferative disease associated with FGFR4 expression, overexpression and/or hyperactivity.

### Claim 78 (depends on 41)

The method according to claim 41, wherein the patient is a mammalian patient, particularly a human patient.

### Claim 79 (depends on 41)

A kit comprising an antibody according to claims 41, associated with FGFR4 expression, overexpression and/or hyperactivity.

### Claim 80 (depends on 79)

The kit according to claim 79, further comprising a further antineoplastic agent.