# US 2018/0022816 A1 · Monoclonal antibodies against her2 epitope

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- Number: US 2018/0022816 A1
- Document ID: US20180022816A1
- Status: Published application
- Kind: A1
- Application number: 15/627,921
- Filed: 2017-06-20
- Published: 2018-01-25
- Earliest claimed: 2010-05-27
- Assignees: Genmab A/S
- Applicants: Genmab A/S
- Inventors: Bart DE GOEIJ; Edward N. VAN DEN BRINK; Simone DE HAIJ; Thilo RIEDL; Rene HOET; Ole BAADSGAARD, D.M.Sc.; David SATIJN; Jan VAN DE WINKEL; Paul PARREN
- Web page: https://patentgrep.com/patent/US20180022816A1

## CPC

- C07K 16/30: from tumour cells
- A61P 35/00: Antineoplastic agents
- C07K 16/32: against translation products of oncogenes
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- 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: 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

Isolated monoclonal antibodies which bind to human epidermal growth factor receptor 2 (HER2), and related antibody-based compositions and molecules, are disclosed. Pharmaceutical compositions comprising the antibodies and therapeutic and diagnostic methods for using the antibodies are also disclosed.

## Claims

### Claim at position 1

1-55. (canceled)

### Claim 56

A nucleic acid encoding a heavy and/or light chain variable region of an antibody which binds to human epidermal growth factor receptor 2 (HER2), wherein the antibody comprises heavy and light chain variable regions selected from the group consisting of:
a) SEQ ID NOs: 1 and 5,
b) SEQ ID NOs: 8 and 12,
c) SEQ ID NOs: 15 and 19,
d) SEQ ID NOs: 22 and 26,
e) SEQ ID NOs: 29 and 33,
f) SEQ ID NOs: 36 and 40,
g) SEQ ID NOs: 43 and 44,
h) SEQ ID NOs: 45 and 46,
i) SEQ ID NOs: 47 and 48,
j) SEQ ID NOs: 49 and 50,
k) SEQ ID NOs: 51 and 52,
l) SEQ ID NOs: 53 and 54, and
m) SEQ ID NOs: 55 and 56.

### Claim 57

An expression vector, or set of expression vectors, which encodes an antibody which blocks the binding of a reference antibody to soluble human epidermal growth factor receptor 2 (HER2), wherein the reference antibody comprises heavy chain variable (VH) and light chain variable (VL) regions selected from the group consisting of:
a) a VH region comprising the sequence of SEQ ID NO:1 and a VL region comprising the sequence of SEQ ID NO:5;
b) a VH region comprising the sequence of SEQ ID NO:8 and a VL region comprising the sequence of SEQ ID NO:12;
c) a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:19;
d) a VH region comprising the sequence of SEQ ID NO:22 and a VL region comprising the sequence of SEQ ID NO:26;
e) a VH region comprising the sequence of SEQ ID NO:29 and a VL region comprising the sequence of SEQ ID NO:33; and
f) a VH region comprising the sequence of SEQ ID NO:36 and a VL region comprising the sequence of SEQ ID NO:40;
optionally when determined as described in Example 14.

### Claim 58 (depends on 57)

The expression vector, or set of expression vectors, of claim 57, which encodes an antibody which binds to HER2, comprising a VH region and a VL region selected from the group consisting of:
a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:2, 3 and 4, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:6, GAS, and SEQ ID NO:7, respectively;
b) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:9, 10 and 11, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:13, DAS, and SEQ ID NO:14, respectively;
c) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:16, 17 and 18, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:20, GAS, and SEQ ID NO:21, respectively;
d) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:23, 24 and 25, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:27, GAS, and SEQ ID NO:28, respectively;
e) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:30, 31 and 32, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:34, GAS, and SEQ ID NO:35, respectively; and
f) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:37, 38 and 39, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:41, GAS, and SEQ ID NO:42, respectively.

### Claim 59 (depends on 58)

The expression vector, or set of expression vectors, of claim 58, comprising a VH region and a VL region selected from the group consisting of:
a) a VH region comprising the sequence of SEQ ID NO:1 and a VL region comprising the sequence of SEQ ID NO:5;
b) a VH region comprising the sequence of SEQ ID NO:8 and a VL region comprising the sequence of SEQ ID NO:12;
c) a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:19;
d) a VH region comprising the sequence of SEQ ID NO:22 and a VL region comprising the sequence of SEQ ID NO:26;
e) a VH region comprising the sequence of SEQ ID NO:29 and a VL region comprising the sequence of SEQ ID NO:33;
f) a VH region comprising the sequence of SEQ ID NO:36 and a VL region comprising the sequence of SEQ ID NO:40; and
g) a variant of any of said antibodies, wherein said variant has at most 1, 2 or 3 amino acid substitutions.

### Claim 60 (depends on 57)

The expression vector, or set of expression vectors, of claim 57, wherein the antibody is a bivalent antibody.

### Claim 61 (depends on 57)

The expression vector, or set of expression vectors, of claim 57, wherein the antibody is an antigen-binding fragment.

### Claim 62 (depends on 57)

The expression vector, or set of expression vectors, of claim 57, wherein the antibody is a full-length antibody.

### Claim 63 (depends on 57)

The expression vector, or set of expression vectors, of claim 57, wherein the antibody is an effector-function-deficient antibody.

### Claim 64 (depends on 57)

The expression vector, or set of expression vectors, of claim 57, wherein the antibody is a monovalent antibody.

### Claim 65 (depends on 64)

The expression vector, or set of expression vectors, of claim 64, wherein the monovalent antibody further comprises a CH region of an immunoglobulin or a fragment thereof comprising the CH2 and CH3 regions, wherein the CH region or fragment thereof has been modified such that the region corresponding to the hinge region and, if the immunoglobulin is not an IgG4 subtype, other regions of the CH region do not comprise any amino acid residues which are capable of forming disulfide bonds with an identical CH region or other covalent or stable non-covalent inter-heavy chain bonds with an identical CH region in the presence of polyclonal human IgG.

### Claim 66 (depends on 57)

The expression vector, or set of expression vectors, of claim 57, which is an IgG1 antibody.

### Claim 67 (depends on 66)

The expression vector, or set of expression vectors, of claim 66, which is an IgG1,κ antibody.

### Claim 68 (depends on 57)

An expression vector, or set of expression vectors, which encodes a bispecific antibody comprising a first antigen-binding region of the antibody of claim 57, and a second antigen-binding region having a different binding specificity than the first antigen-binding region.

### Claim 69 (depends on 68)

The expression vector, or set of expression vectors, of claim 68, wherein the second-antigen binding region binds to CD3.

### Claim 70 (depends on 68)

The expression vector, or set of expression vectors, claim 68, wherein the second antigen-binding site binds to a molecule selected from the group consisting of: a cancer- or tumor-associated antigen; a cancer-associated integrin; a T cell and/or NK cell antigen; an angiogenic factor, receptor for an angiogenic factor, or other cancer-associated growth factor; and a receptor associated with cancer progression.

### Claim 71 (depends on 70)

The expression vector, or set of expression vectors, of claim 70, wherein the cancer- or tumor-associated antigen is selected from the group consisting of: a carcinoembryonic antigen, prostate specific antigen, renal antigen, α-fetoprotein, CTL-recognized antigen on melanoma, a CT antigen, a mucin antigen, a ganglioside antigen, tyrosinase, gp75, c-Met, c-myc, Mart1, MelanA, MUM-1, MUM-2, MUM-3, HLA-B7, and Ep-CAM.

### Claim 72 (depends on 71)

The expression vector, or set of expression vectors, of claim 71, wherein:
a) the CT antigen is selected from the group consisting of: MAGE-B5, MAGE-B6, MAGE-C2, MAGE-C3, MAGE-D, Mage-12, CT10, NY-ESO-1, SSX-2, GAGE, BAGE, MAGE, and SAGE;
b) the mucin antigen is MUC1 or mucin-CA125;
c) the cancer-associated integrin is α5β3 integrin;
d) the T cell and/or NK cell antigen is CD3 or CD16;
e) the angiogenic factor or other cancer-associated growth factor is selected from the group consisting of vascular endothelial growth factor, fibroblast growth factor, epidermal growth factor, angiogenin, vascular endothelial growth factor receptor, fibroblast growth factor receptor, epidermal growth factor receptor, and angiogenin receptor; or
f) the receptor associated with cancer progression is selected from the group consisting of HER1, HER3, and HER4.

### Claim 73 (depends on 68)

The expression vector, or set of expression vectors, of claim 68, wherein the second antigen-binding region binds to a different site on HER2 than the first antigen-binding region.

### Claim 74 (depends on 73)

The expression vector, or set of expression vectors, of claim 73, wherein the second antigen-binding region cross-blocks the binding of trastuzumab, pertuzumab, F5, or C1 to HER2.

### Claim 75

A recombinant host cell which produces an antibody which blocks the binding of a reference antibody to soluble human epidermal growth factor receptor 2 (HER2), wherein the reference antibody comprises heavy chain variable (VH) and light chain variable (VL) regions selected from the group consisting of:
a) a VH region comprising the sequence of SEQ ID NO:1 and a VL region comprising the sequence of SEQ ID NO:5;
b) a VH region comprising the sequence of SEQ ID NO:8 and a VL region comprising the sequence of SEQ ID NO:12;
c) a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:19;
d) a VH region comprising the sequence of SEQ ID NO:22 and a VL region comprising the sequence of SEQ ID NO:26;
e) a VH region comprising the sequence of SEQ ID NO:29 and a VL region comprising the sequence of SEQ ID NO:33; and
f) a VH region comprising the sequence of SEQ ID NO:36 and a VL region comprising the sequence of SEQ ID NO:40;
optionally when determined as described in Example 14.

### Claim 76 (depends on 75)

The recombinant host cell of claim 75, wherein the antibody comprises heavy chain variable (VH) and light chain variable (VL) regions selected from the group consisting of:
a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:2, 3 and 4, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:6, GAS, and SEQ ID NO:7, respectively;
b) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:9, 10 and 11, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:13, DAS, and SEQ ID NO:14, respectively;
c) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:16, 17 and 18, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:20, GAS, and SEQ ID NO:21, respectively;
d) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:23, 24 and 25, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:27, GAS, and SEQ ID NO:28, respectively;
e) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:30, 31 and 32, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:34, GAS, and SEQ ID NO:35, respectively; and
f) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:37, 38 and 39, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:41, GAS, and SEQ ID NO:42, respectively.

### Claim 77 (depends on 76)

The recombinant host cell of claim 76, wherein the antibody comprises a VH region and a VL region selected from the group consisting of:
a) a VH region comprising the sequence of SEQ ID NO:1 and a VL region comprising the sequence of SEQ ID NO:5;
b) a VH region comprising the sequence of SEQ ID NO:8 and a VL region comprising the sequence of SEQ ID NO:12;
c) a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:19;
d) a VH region comprising the sequence of SEQ ID NO:22 and a VL region comprising the sequence of SEQ ID NO:26;
e) a VH region comprising the sequence of SEQ ID NO:29 and a VL region comprising the sequence of SEQ ID NO:33;
f) a VH region comprising the sequence of SEQ ID NO:36 and a VL region comprising the sequence of SEQ ID NO:40; and
g) a variant of any of said antibodies, wherein said variant has at most 1, 2 or 3 amino acid substitutions.

### Claim 78 (depends on 75)

A method for producing an antibody, said method comprising the steps of
a) culturing a recombinant host cell of claim 75, and
b) purifying the antibody from the culture media.

### Claim 79 (depends on 78)

The method of claim 78, wherein the recombinant host cell produces an antibody comprising heavy chain variable (VH) and light chain variable (VL) regions selected from the group consisting of:
a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:2, 3 and 4, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:6, GAS, and SEQ ID NO:7, respectively;
b) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:9, 10 and 11, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:13, DAS, and SEQ ID NO:14, respectively;
c) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:16, 17 and 18, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:20, GAS, and SEQ ID NO:21, respectively;
d) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:23, 24 and 25, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:27, GAS, and SEQ ID NO:28, respectively;
e) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:30, 31 and 32, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:34, GAS, and SEQ ID NO:35, respectively; and
f) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:37, 38 and 39, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:41, GAS, and SEQ ID NO:42, respectively.

### Claim 80 (depends on 79)

The method of claim 79, wherein the recombinant host cell produces an antibody comprising a VH region and a VL region selected from the group consisting of:
a) a VH region comprising the sequence of SEQ ID NO:1 and a VL region comprising the sequence of SEQ ID NO:5;
b) a VH region comprising the sequence of SEQ ID NO:8 and a VL region comprising the sequence of SEQ ID NO:12;
c) a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:19;
d) a VH region comprising the sequence of SEQ ID NO:22 and a VL region comprising the sequence of SEQ ID NO:26;
e) a VH region comprising the sequence of SEQ ID NO:29 and a VL region comprising the sequence of SEQ ID NO:33;
f) a VH region comprising the sequence of SEQ ID NO:36 and a VL region comprising the sequence of SEQ ID NO:40; and
g) a variant of any of said antibodies, wherein said variant has at most 1, 2 or 3 amino acid substitutions.

### Claim 81 (depends on 78)

The method of claim 78, wherein the antibody is a bivalent antibody.

### Claim 82 (depends on 78)

The method of claim 78, wherein the antibody is an antigen-binding fragment.

### Claim 83 (depends on 78)

The method of claim 78, wherein the antibody is a full-length antibody.

### Claim 84 (depends on 78)

The method of claim 78, wherein the antibody is an effector-function-deficient antibody.

### Claim 85 (depends on 78)

The method of claim 78, wherein the antibody is a monovalent antibody.

### Claim 86 (depends on 85)

The method of claim 85, wherein the monovalent antibody further comprises a CH region of an immunoglobulin or a fragment thereof comprising the CH2 and CH3 regions, wherein the CH region or fragment thereof has been modified such that the region corresponding to the hinge region and, if the immunoglobulin is not an IgG4 subtype, other regions of the CH region do not comprise any amino acid residues which are capable of forming disulfide bonds with an identical CH region or other covalent or stable non-covalent inter-heavy chain bonds with an identical CH region in the presence of polyclonal human IgG.

### Claim 87 (depends on 78)

The method of claim 78, which is an IgG1 antibody.

### Claim 88 (depends on 87)

The method of claim 87, which is an IgG1,κ antibody.

### Claim 89 (depends on 78)

The method of claim 78, wherein the recombinant host cell produces a bispecific antibody comprising a first antigen-binding region of an antibody which blocks the binding of a reference antibody to soluble human epidermal growth factor receptor 2 (HER2), wherein the reference antibody comprises heavy chain variable (VH) and light chain variable (VL) regions selected from the group consisting of:
a) a VH region comprising the sequence of SEQ ID NO:1 and a VL region comprising the sequence of SEQ ID NO:5;
b) sa VH region comprising the sequence of SEQ ID NO:8 and a VL region comprising the sequence of SEQ ID NO:12;
c) a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:19;
d) a VH region comprising the sequence of SEQ ID NO:22 and a VL region comprising the sequence of SEQ ID NO:26;
e) a VH region comprising the sequence of SEQ ID NO:29 and a VL region comprising the sequence of SEQ ID NO:33; and
f) a VH region comprising the sequence of SEQ ID NO:36 and a VL region comprising the sequence of SEQ ID NO:40;
optionally when determined as described in Example 14,
and a second antigen-binding region having a different binding specificity than the first antigen-binding region.

### Claim 90 (depends on 89)

The method of claim 89, wherein the second-antigen binding region binds to CD3.

### Claim 91 (depends on 89)

The method of claim 89, wherein the second antigen-binding site binds to a molecule selected from the group consisting of: a cancer- or tumor-associated antigen; a cancer-associated integrin; a T cell and/or NK cell antigen; an angiogenic factor, receptor for an angiogenic factor, or other cancer-associated growth factor; and a receptor associated with cancer progression.

### Claim 92 (depends on 91)

The method of claim 91, wherein the cancer- or tumor-associated antigen is selected from the group consisting of: a carcinoembryonic antigen, prostate specific antigen, renal antigen, α-fetoprotein, CTL-recognized antigen on melanoma, a CT antigen, a mucin antigen, a ganglioside antigen, tyrosinase, gp75, c-Met, c-myc, Mart1, MelanA, MUM-1, MUM-2, MUM-3, HLA-B7, and Ep-CAM.

### Claim 93 (depends on 92)

The method of claim 92, wherein:
a) the CT antigen is selected from the group consisting of: MAGE-B5, MAGE-B6, MAGE-C2, MAGE-C3, MAGE-D, Mage-12, CT10, NY-ESO-1, SSX-2, GAGE, BAGE, MAGE, and SAGE;
b) the mucin antigen is MUC1 or mucin-CA125;
c) the cancer-associated integrin is a5133 integrin;
d) the T cell and/or NK cell antigen is CD3 or CD16;
e) the angiogenic factor or other cancer-associated growth factor is selected from the group consisting of vascular endothelial growth factor, fibroblast growth factor, epidermal growth factor, angiogenin, vascular endothelial growth factor receptor, fibroblast growth factor receptor, epidermal growth factor receptor, and angiogenin receptor; or
f) the receptor associated with cancer progression is selected from the group consisting of HER1, HER3, and HER4.

### Claim 94 (depends on 89)

The method of claim 89, wherein the second antigen-binding region binds to a different site on HER2 than the first antigen-binding region.

### Claim 95 (depends on 94)

The method of claim 94, wherein the second antigen-binding region cross-blocks the binding of trastuzumab, pertuzumab, F5, or C1 to HER2.