# US 11,305,012 B2 · Binding molecules specific for HER3 and uses thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,305,012 B2
- Document ID: US11305012B2
- Status: Granted
- Kind: B2
- Application number: 15/023,858
- Filed: 2014-09-23
- Published: 2016-08-18
- Granted: 2022-04-19
- Earliest claimed: 2013-09-24
- Assignees: MedImmune, LLC
- Applicants: MedImmune, LLC
- Inventors: Partha S. Chowdhury; David Tice; Zhan Xiao; Philipp Steiner; Krista Kinneer; Marlon Rebelatto; Andrew Pierce
- Web page: https://patentgrep.com/patent/US11305012B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39591: {Stabilisation, fragmentation}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6857: {the tumour determinant being from lung cancer cell}
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/30: from tumour cells
- C07K 16/3015: {Breast}
- C07K 16/3023: {Lung}
- C07K 16/32: against translation products of oncogenes
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/54: F(ab')2
- C07K 2317/55: Fab or Fab'
- 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 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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
- 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)
- 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)

## Abstract

Provided herein are antibodies and antigen binding fragments thereof that bind the extracellular domain of the HER3 receptor and inhibit various HER3 receptor related functions via ligand-dependent and/or ligand-independent mechanisms. Also provided are compositions with increased half-life, as well as compositions and methods for diagnosing and treating diseases associated with HER3 mediated signal transduction.

## Claims

### Claim 1

A method of resensitizing a HER3-expressing tumor characterized by unregulated cell growth or HER3-expressing tumor cell characterized by unregulated cell growth in a subject to a HER targeted therapy, comprising a) administering to the subject a therapeutically effective amount of an antibody or antigen binding fragment thereof which specifically binds to an epitope within the extracellular domain of HER3, wherein the tumor or tumor cell had previously acquired resistance to the HER targeted therapy following treatment with the HER targeted therapy, wherein the HER targeted therapy is an EGFR targeted therapy, and wherein the antibody or antigen binding fragment thereof is a monoclonal antibody or antigen binding fragment thereof that comprises
(A) an antibody VL, wherein the VL comprises the amino acid sequence:
[FW1]X1GSX2SNIGLNYVS(SEQ ID NO: 49)[FW2]RNNQRPS(SEQ ID NO: 50)[FW3]AAWDDX3X4X5GEX6(SEQ ID NO: 51)[FW4]
wherein [FW1], [FW2], [FW3] and [FW4] represent VL framework regions, and wherein
(a) X1 represents amino acid residues Arginine (R) or Serine (S),
(b) X2 represents amino acid residues Serine (S) or Leucine (L),
(c) X3 represents amino acid residues Serine (S) or Glycine (G),
(d) X4 represents amino acid residues Leucine (L) or Proline (P),
(e) X5 represents amino acid residues Arginine (R), Isoleucine (I), Proline (P) or Serine (S), and
(f) X6 represents amino acid residues Valine (V) or Alanine (A), and
(B) an antibody VH, wherein the VH comprises the amino acid sequence:
[FW5]YYYMQ(SEQ ID NO: 52)[FW6]X7IGSSGGVTNYADSVKG(SEQ ID NO: 53)[FW7]VGLGDAFDI(SEQ ID NO: 54)[FW8] wherein [FW5], [FW6], [FW7] and [FW8] represent VH framework regions, and wherein X7 represents amino acid residues Tyrosine (Y), Isoleucine (I) or Valine (V); and b) simultaneously administering to the subject a therapeutically effective amount of the HER targeted therapy.

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody or antigen binding fragment thereof is administered for a first period of time and a second period of time, wherein there is a period of rest between the first period of time and the second period of time, wherein the antibody or antigen binding fragment thereof is not administered to the subject during the period of rest.

### Claim 3 (depends on 2)

The method of claim 2, wherein the HER targeted therapy is administered during the first period of time and the second period of time, and wherein the HER targeted therapy is not administered to the subject during the period of rest.

### Claim 4 (depends on 1)

The method of claim 1, wherein the EGFR targeted therapy is cetuximab.

### Claim 5 (depends on 1)

The method of claim 1, wherein the tumor or tumor cell is a lung cancer tumor or tumor cell, colorectal cancer tumor or tumor cell, or head and neck cancer tumor or tumor cell.

### Claim 6 (depends on 1)

The method of claim 1, wherein the antibody or antigen binding fragment comprises a VL comprising SEQ ID NO: 3 and a VH comprising SEQ ID NO: 2.

### Claim 7 (depends on 6)

The method of claim 6, wherein the antibody or antigen binding fragment comprises a heavy chain constant region or fragment thereof.

### Claim 8 (depends on 7)

The method of claim 7, wherein the heavy chain constant region or fragment thereof is an IgG constant region.

### Claim 9 (depends on 8)

The method of claim 8, wherein the IgG constant region is an IgG1 constant region.

### Claim 10 (depends on 6)

The method of claim 6, wherein the antibody or antigen binding fragment comprises a light chain constant region selected from the group consisting of a human kappa constant region and a human lambda constant region.

### Claim 11 (depends on 8)

The method of claim 8, wherein the IgG constant region comprises one or more amino acid substitutions relative to a wild-type IgG constant region wherein the modified IgG has an increased half-life compared to the half-life of an IgG having the wild-type IgG constant region.

### Claim 12 (depends on 8)

The method of claim 8, wherein the IgG constant region is a human IgG constant region that comprises amino acid substitutions relative to a wild-type human IgG constant region at positions 252, 254, and 256, wherein
(a) the amino acid at position 252 is substituted with Tyrosine (Y),
(b) the amino acid at position 254 is substituted with Threonine (T), and
(c) the amino acid at position 256 is substituted with Glutamic acid (E),
wherein the numbering is according to the EU index as set forth in Kabat.

### Claim 13 (depends on 1)

The method of claim 1, wherein the antibody is a fully human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, a multispecific antibody, or an antigen-binding fragment thereof.

### Claim 14 (depends on 1)

The method of claim 1, which antigen binding fragment is a Fv, Fab, F(ab′)2, Fab′, dsFv, scFv, and sc(Fv)2.