# US 10,479,831 B2 · BCR-complex-specific antibodies and methods of using same

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- Number: US 10,479,831 B2
- Document ID: US10479831B2
- Status: Granted
- Kind: B2
- Application number: 15/609,710
- Filed: 2017-05-31
- Published: 2018-02-22
- Granted: 2019-11-19
- Earliest claimed: 2008-04-02
- Assignees: MacroGenics, Inc.
- Applicants: MacroGenics, Inc.
- Inventors: Leslie S. Johnson; Ling Huang
- Web page: https://patentgrep.com/patent/US10479831B2

## CPC

- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- 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

## Abstract

This invention relates to chimeric and humanized antibodies that specifically bind the BCR complex, and particularly chimeric and humanized antibodies to the BCR complex. The invention also relates to methods of using the antibodies and compositions comprising them in the diagnosis, prognosis and therapy of diseases such as cancer, autoimmune diseases, inflammatory disorders, and infectious disease.

## Claims

### Claim 1

A method of treating an autoimmune or immune-mediated inflammatory disease in a subject, comprising administering to said subject a therapeutically effective amount of a diabody that binds human BCR complex, wherein said diabody comprises:
(I) an amino acid sequence of an immunoglobulin light chain variable region (VL) that is a humanized variant of BCC VL that comprises:
(A) a modification at Kabat residue 37;
(B) a modification at Kabat residue 45; or
(C) both (A) and (B); and
(II) an amino acid sequence of an immunoglobulin heavy chain variable region (VH) that is a humanized variant of BCC VH that comprises a modification of one or more of Kabat residues 48, 62, 66, 67, 68, 69, 70, 71 or 73.

### Claim 2 (depends on 1)

The method of claim 1, wherein said VL has:
(A) a leucine substitution at Kabat residue 37;
(B) a lysine or an asparagine substitution at Kabat residue 45; or
(C) both (A) and (B).

### Claim 3 (depends on 1)

The method of claim 1, wherein said VL has a leucine at Kabat residue 37 and a lysine at Kabat residue 45.

### Claim 4 (depends on 1)

The method of claim 1, wherein said VL has a leucine at Kabat residue 37 and an asparagine at Kabat residue 45.

### Claim 5 (depends on 1)

The method of claim 1, wherein said VL comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, and SEQ ID NO:20.

### Claim 6 (depends on 1)

The method of claim 1, wherein said VH comprises one or more modifications selected from the group consisting of:
(A) an isoleucine substitution at Kabat residue 48;
(B) a lysine substitution at Kabat residue 62;
(C) a lysine substitution at Kabat residue 66;
(D) an alanine substitution at Kabat residue 67;
(E) a leucine substitution at Kabat residue 69;
(F) a valine substitution at Kabat residue 71; and
(G) a lysine substitution at Kabat residue 73.

### Claim 7 (depends on 1)

The method of claim 1, wherein said VH comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, and SEQ ID NO:36.

### Claim 8 (depends on 1)

The method of claim 1, wherein:
(I) said VL comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, and SEQ ID NO:20; and
(II) said VH comprises an amino acid sequence selected from the group consisting of SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, and SEQ ID NO:36.

### Claim 9 (depends on 8)

The method of claim 8, wherein said VL comprises the amino acid sequence of SEQ ID NO:16 and said VH comprises the amino acid sequence of SEQ ID NO:34.

### Claim 10 (depends on 1)

The method of claim 1, wherein said diabody is operably linked to a heterologous polypeptide.

### Claim 11 (depends on 1)

The method of claim 1, wherein said diabody comprises an epitope binding site that binds CD32B.

### Claim 12 (depends on 1)

The method of claim 1, wherein said diabody comprises an Fc domain or portion thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein said autoimmune or immune-mediated inflammatory disease is selected from the group consisting of Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, vasculitis, asthma, eczema and atopic dermatitis, fibrosis, graft rejection, graft-versus-host-disease, and inflammatory bowel disease.

### Claim 14 (depends on 1)

The method of claim 1, comprising the further step of administering an additional therapeutic agent with said diabody that binds human BCR complex.

### Claim 15 (depends on 14)

The method of claim 14, wherein said additional therapeutic agent is selected from the group consisting of an anti-angiogenic agent, an anti-neoplastic agent, a chemotherapeutic agent, and a cytotoxic agent.