# US 2013/0156784 A1 · Compositions Using Antibodies Directed To GPNMB 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 2013/0156784 A1
- Document ID: US20130156784A1
- Status: Published application
- Kind: A1
- Application number: 13/544,526
- Filed: 2012-07-09
- Published: 2013-06-20
- Earliest claimed: 2008-08-20
- Inventors: Michael Jeffers; William LaRochelle
- Web page: https://patentgrep.com/patent/US20130156784A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/35: having six-membered rings with one oxygen as the only ring hetero atom
- A61K 31/426: 1,3-Thiazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4706: 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/52: Purines, e.g. adenine
- A61K 31/54: having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K 33/20: Elemental chlorine; Inorganic compounds releasing chlorine
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- C07K 16/30: from tumour cells
- C07K 2317/21: from primates, e.g. man
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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

The present invention relates to antibodies, including fully human monoclonal antibodies, with specificity to GPNMB, and uses of such antibodies. The present invention further provides compositions that increase expression of GPNMB on the surface of tumor cells, and methods of using such compositions to increase the anti-cancer activity or other therapeutic efficacy of the antibodies and immunoconjugates provided herein.

## Claims

### Claim 1

A pharmaceutical composition comprising an isolated monoclonal antibody that specifically binds to GPNMB and a second agent that increases expression of GPNMB on a tumor cell or decreases shedding of GPNMB by a tumor cell.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the second agent is selected from an inhibitor of the ERK pathway, a tyrosine kinase inhibitor, an inhibitor of p38 MAPK, a lysosomotropic weak base and an inhibitor of GPNMB shedding.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the antibody is a human monoclonal antibody.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 20, 38, 56, 74, 92, 110, 128, 146, 164, 182, 200, 218, 236, 253, 256, 260, 265, 270, 274, 277, 281 and 285; and the antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 11, 29, 47, 65, 83, 101, 119, 137, 155, 173, 191, 209, 227 and 245.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the antibody comprises
(a) a VH CDR1 region comprising the amino acid sequence of SEQ ID NO: 4, 22, 40, 58, 76, 94, 112, 130, 148, 166, 184, 202, 220, 238, 254, 257, 261, 266, 271, 278, 282 or 286;
(b) a VH CDR2 region comprising the amino acid sequence of SEQ ID NO: 6, 24, 42, 60, 78, 96, 114, 132, 150, 168, 186, 204, 222, 240, 255, 258, 262, 267, 272, 275, 279, 283 or 287;
(c) a VH CDR3 region comprising the amino acid sequence of SEQ ID NO: 8, 26, 44, 62, 80, 98, 116, 134, 152, 170, 188, 206, 224, 242, 259, 263, 264, 268, 269, 273, 276, 280, 284 or 288;
(d) a VL CDR1 region comprising the amino acid sequence of SEQ ID NO: 13, 31, 49, 67, 85, 103, 121, 139, 157, 175, 193, 211, 229 or 247;
(e) a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 15, 33, 51, 69, 87, 105, 123, 141, 159, 177, 195, 213, 231, 249 or 279;
(f) a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, 35, 53, 71, 89, 107, 125, 143, 161, 179, 197, 215, 233 or 251; and
wherein said antibody binds GPNMB.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the antibody is an IgG1 antibody.

### Claim 7 (depends on 1)

The composition of claim 1, wherein said antibody is conjugated to a cytotoxic agent.

### Claim 8 (depends on 7)

The composition of claim 7, wherein the cytotoxic agent is auristatin E (dolastatin-10) or a derivative thereof.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the tumor cell is a melanoma cell or a glioblastoma cell.

### Claim 10 (depends on 9)

The composition of claim 9, wherein the melanoma cell comprise the NRAS or BRAF mutation.

### Claim 11 (depends on 2)

The composition of claim 2, wherein the ERK pathway inhibitor is selected from A6355 (3-(2-Aminoethyl)-5-((4-ethoxyphenyl)methylene)-2,4-thiazolidinedione hydrochloride) and FR180204 ((5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-amine)).

### Claim 12 (depends on 2)

The composition of claim 2, wherein the tyrosine kinase inhibitor is imatinib.

### Claim 13 (depends on 2)

The composition of claim 2, wherein the lysosomotropic weak base is ammonium chloride or chloroquine.

### Claim 14 (depends on 2)

The composition of claim 2, wherein the inhibitor of GPNMB shedding is monensin.

### Claim 15 (depends on 2)

The composition of claim 2, wherein the p38 MAK inhibitor is SB202190 (4-[4-(4-Fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]phenol) or SB203580 (4-[5-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine).

### Claim 16

A method for enhancing expression of GPNMB on the surface of a tumor cell, comprising contacting a tumor cell with a composition comprising an isolated monoclonal antibody that specifically binds to GPNMB and a second agent selected from an inhibitor of the ERK pathway, a tyrosine kinase inhibitor, an inhibitor of p38 MAPK, a lysosomotropic weak base and an inhibitor of GPNMB shedding, wherein the composition is present in an amount sufficient to increase expression of GPNMB on the tumor cell or decrease shedding of GPNMB by the tumor cell.

### Claim 17 (depends on 16)

The method of claim 16, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 20, 38, 56, 74, 92, 110, 128, 146, 164, 182, 200, 218, 236, 253, 256, 260, 265, 270, 274, 277, 281 and 285; and the antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 11, 29, 47, 65, 83, 101, 119, 137, 155, 173, 191, 209, 227 and 245.

### Claim 18 (depends on 16)

The method of claim 16, wherein the antibody comprises
(a) a VH CDR1 region comprising the amino acid sequence of SEQ ID NO: 4, 22, 40, 58, 76, 94, 112, 130, 148, 166, 184, 202, 220, 238, 254, 257, 261, 266, 271, 278, 282 or 286;
(b) a VH CDR2 region comprising the amino acid sequence of SEQ ID NO: 6, 24, 42, 60, 78, 96, 114, 132, 150, 168, 186, 204, 222, 240, 255, 258, 262, 267, 272, 275, 279, 283 or 287;
(c) a VH CDR3 region comprising the amino acid sequence of SEQ ID NO: 8, 26, 44, 62, 80, 98, 116, 134, 152, 170, 188, 206, 224, 242, 259, 263, 264, 268, 269, 273, 276, 280, 284 or 288;
(d) a VL CDR1 region comprising the amino acid sequence of SEQ ID NO: 13, 31, 49, 67, 85, 103, 121, 139, 157, 175, 193, 211, 229 or 247;
(e) a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 15, 33, 51, 69, 87, 105, 123, 141, 159, 177, 195, 213, 231, 249 or 279;
(f) a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, 35, 53, 71, 89, 107, 125, 143, 161, 179, 197, 215, 233 or 251; and
wherein said antibody binds GPNMB.

### Claim 19 (depends on 16)

The method of claim 16, wherein said antibody is conjugated to auristatin E (dolastatin-10) or a derivative thereof.

### Claim 20 (depends on 16)

The method of claim 16, wherein the tumor cell is a glioblastoma cell or a melanoma cell comprising the NRAS or BRAF mutation.

### Claim 21 (depends on 16)

The method of claim 16, wherein the second agent is selected from A6355 (3-(2-Aminoethyl)-5-((4-ethoxyphenyl)methylene)-2,4-thiazolidinedione hydrochloride); FR180204 ((5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-amine)); imatinib; ammonium chloride; chloroquine; monensin; SB202190 (4-[4-(4-Fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]phenol); and SB203580 (4-[5-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine).

### Claim 22

A method of treating or preventing a disease associated with overexpression of GPNMB comprising administering to a subject in need thereof an effective amount of a composition comprising an isolated monoclonal antibody that specifically binds to GPNMB and a second agent selected from an inhibitor of the ERK pathway, a tyrosine kinase inhibitor, an inhibitor of p38 MAPK, a lysosomotropic weak base and an inhibitor of GPNMB shedding.

### Claim 23 (depends on 22)

The method of claim 22, wherein said disease is melanoma or a neoplasm of CNS system.

### Claim 24 (depends on 22)

The method of claim 22, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 20, 38, 56, 74, 92, 110, 128, 146, 164, 182, 200, 218, 236, 253, 256, 260, 265, 270, 274, 277, 281 and 285; and the antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 11, 29, 47, 65, 83, 101, 119, 137, 155, 173, 191, 209, 227 and 245.

### Claim 25 (depends on 22)

The method of claim 22, wherein the antibody comprises
(a) a VH CDR1 region comprising the amino acid sequence of SEQ ID NO: 4, 22, 40, 58, 76, 94, 112, 130, 148, 166, 184, 202, 220, 238, 254, 257, 261, 266, 271, 278, 282 or 286;
(b) a VH CDR2 region comprising the amino acid sequence of SEQ ID NO: 6, 24, 42, 60, 78, 96, 114, 132, 150, 168, 186, 204, 222, 240, 255, 258, 262, 267, 272, 275, 279, 283 or 287;
(c) a VH CDR3 region comprising the amino acid sequence of SEQ ID NO: 8, 26, 44, 62, 80, 98, 116, 134, 152, 170, 188, 206, 224, 242, 259, 263, 264, 268, 269, 273, 276, 280, 284 or 288;
(d) a VL CDR1 region comprising the amino acid sequence of SEQ ID NO: 13, 31, 49, 67, 85, 103, 121, 139, 157, 175, 193, 211, 229 or 247;
(e) a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 15, 33, 51, 69, 87, 105, 123, 141, 159, 177, 195, 213, 231, 249 or 279;
(f) a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, 35, 53, 71, 89, 107, 125, 143, 161, 179, 197, 215, 233 or 251; and
wherein said antibody binds GPNMB.

### Claim 26 (depends on 22)

The method of claim 22, wherein said antibody is conjugated to auristatin E (dolastatin-10) or a derivative thereof.

### Claim 27 (depends on 22)

The method of claim 22, wherein the tumor cell is a glioblastoma cell or a melanoma cell comprising the NRAS or BRAF mutation.

### Claim 28 (depends on 22)

The method of claim 22, wherein the second agent is selected from A6355 (3-(2-Aminoethyl)-5-((4-ethoxyphenyl)methylene)-2,4-thiazolidinedione hydrochloride); FR180204 ((5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridazin-3-amine)); imatinib; ammonium chloride; chloroquine; monensin; SB202190 (4-[4-(4-Fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]phenol); and SB203580 (4-[5-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine).