# US 2014/0193405 A1 · Humanized anti-cd40 antibodies

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- Number: US 2014/0193405 A1
- Document ID: US20140193405A1
- Status: Published application
- Kind: A1
- Application number: 14/202,923
- Filed: 2014-03-10
- Published: 2014-07-10
- Earliest claimed: 2005-05-26
- Assignees: Seattle Genetics, Inc.; Genentech, Inc.
- Inventors: Leonard G. Presta; Lori Y. O'Connell; Svetlana O. Doronina
- Web page: https://patentgrep.com/patent/US20140193405A1

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/55: Fab or Fab'
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- 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

Provided are humanized anti-CD40 antibodies and antigen-binding fragments and methods for treating disease characterized by expression of CD40 antigen.

## Claims

### Claim 1

An isolated antibody or antigen-binding fragment that specifically binds to human CD40, comprising a humanized heavy chain variable domain comprising a framework region having an amino acid sequence at least 90% identical to the amino acid sequence of the framework region of the human variable domain heavy chain subgroup III concensus amino acid sequence of SEQ ID NO:2, and comprising at least one CDR having an amino acid sequence at least 90% identical to a corresponding heavy chain CDR of SEQ ID NO:3.

### Claim 2

An isolated antibody or antigen-binding fragment that specifically binds to human CD40, comprising a humanized light chain variable domain comprising a framework region having an amino acid sequence at least 90% identical to the framework region of the human variable domain light chain subgroup kappa I concensus amino acid sequence of SEQ ID NO:13, and comprising at least one CDR having an amino acid sequence at least 90% identical to a corresponding light chain CDR of SEQ ID NO:14.

### Claim 3 (depends on 1)

The antibody or antigen-binding fragment of claim 1, further comprising humanized light chain variable domain comprising a framework region comprising an amino acid sequence at least 90% identical to the framework region of the human variable domain light chain subgroup kappa I concensus amino acid sequence of SEQ ID NO:13 comprising at least one CDR having an amino acid sequence at least 90% identical to a corresponding light chain CDR of SEQ ID NO:14.

### Claim 4 (depends on 1)

The antibody or antigen-binding fragment of claim 1, wherein each heavy chain CDR is at least 90% identical to the corresponding heavy chain CDR of SEQ ID NO:3.

### Claim 5 (depends on 4)

The antibody or antigen-binding fragment of claim 4, wherein the heavy chain CDRs comprise the amino acid sequences of the corresponding heavy chain CDRs of SEQ ID NO:3.

### Claim 6 (depends on 2, 3)

The antibody or antigen-binding fragment of claim 2 or 3, wherein each light chain CDR is at least 90% identical to the corresponding light chain CDR of SEQ ID NO:14.

### Claim 7 (depends on 6)

The antibody or antigen-binding fragment of claim 6, wherein the light chain CDRs comprise the amino acid sequences of the light chain CDRs of SEQ ID NO:14.

### Claim 8 (depends on 1)

The antibody or antigen-binding fragment of claim 1, comprising the heavy chain variable domain amino acid sequence of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, or SEQ ID NO:11.

### Claim 9 (depends on 2)

The antibody or antigen-binding fragment of claim 2, comprising the light chain variable domain amino acid sequence of SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:16.

### Claim 10 (depends on 3)

The antibody or antigen-binding fragment of claim 3, comprising the heavy chain variable domain amino acid sequence of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, or SEQ ID NO:11, and the light chain variable domain amino acid sequence of SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:16.

### Claim 11 (depends on 1, 3)

The antibody or antigen-binding fragment of claim 1 or 3, further comprising a human IgG constant region.

### Claim 12 (depends on 11)

The antibody or antigen-binding fragment of claim 11, wherein the isotype of the IgG constant region is IgG1, IgG2, IgG3, or IgG4.

### Claim 13 (depends on 12)

The antibody or antigen-binding fragment of claim 12, wherein the isotype of the IgG constant region is IgG1.

### Claim 14 (depends on 2, 3)

The antibody or antigen-binding fragment of claim 2 or 3, further comprising a light chain constant domain.

### Claim 15 (depends on 14)

The antibody or antigen-binding fragment of claim 14, wherein the light chain constant domain is a kappa constant domain.

### Claim 16 (depends on 10)

The antibody or antigen-binding fragment of claim 10, wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:3 and SEQ ID NO:14, respectively; SEQ ID NO:4 and SEQ ID NO:14, respectively; SEQ ID NO:5 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:14, respectively; SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:8 and SEQ ID NO:14, respectively; SEQ ID NO:9 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:15, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:7 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:14, respectively; SEQ ID NO:11 and SEQ ID NO:14, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO:11 and SEQ ID NO:16, respectively.

### Claim 17 (depends on 10)

The antibody or antigen-binding fragment of claim 10, wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:7 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:14, respectively; SEQ ID NO:11 and SEQ ID NO:14, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO: 11 and SEQ ID NO:16, respectively.

### Claim 18 (depends on 10)

The antibody or antigen-binding fragment of claim 10, wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO: 11 and SEQ ID NO:16, respectively.

### Claim 19 (depends on 10)

The antibody or antigen-binding fragment of claim 10, wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:3 and SEQ ID NO:14, respectively.

### Claim 20 (depends on 10)

The antibody or antigen-binding fragment of claim 10, wherein the heavy chain variable domain and the light chain variable domain comprise the amino acid sequences of SEQ ID NO:10 and SEQ ID NO:16, respectively.

### Claim 21 (depends on 16, 17, 18, 19, 20)

The antibody of any one of claims 16-20, wherein the antibody further comprises a human immunoglobulin constant region.

### Claim 22 (depends on 21)

The antibody of claim 21, comprising the heavy chain and the light chain amino acid sequences set forth in SEQ ID NO:19 and SEQ ID NO:22, respectively.

### Claim 23 (depends on 21)

The antibody of claim 21, which is hu sgn-0, hu sgn-1, hu sgn-2, hu sgn-4, hu sgn-14, hu sgn-15, hu sgn-16, hu sgn-17, hu sgn-18, hu sgn-19, hu sgn-22, hu sgn-23, hu sgn-26 or hu sgn-27.

### Claim 24 (depends on 1, 2, 3)

The antibody or antigen-binding fragment of any one of claims 1-3, which is an antigen-binding antibody fragment.

### Claim 25 (depends on 24)

The antigen binding fragment of claim 24, wherein the antibody fragment is a Fab, a Fab′, a F(ab′)2, a Fv fragment, a diabody, a single-chain antibody, an scFv fragment or an scFv-Fc.

### Claim 26 (depends on 1, 2, 3)

The antibody or antigen-binding fragment of any one of claims 1-3, further comprising a detectable label.

### Claim 27 (depends on 1, 2, 3)

The antibody or antigen-binding fragment of any one of claims 1-3, wherein the antibody is conjugated to a chemotherapeutic agent.

### Claim 28 (depends on 27)

The antibody or antigen-binding fragment of claim 27, wherein the chemotherapeutic agent is an auristatin.

### Claim 29 (depends on 28)

The antibody or antigen-binding fragment of claim 28, wherein the auristatin is MMAE or MMAF.

### Claim 30 (depends on 1, 2, 3)

A kit comprising in a container the antibody or antigen binding fragment of any one of claims 1-3, and optionally instructions for using the antibody to detect CD40 protein in a biological sample.

### Claim 31 (depends on 1, 2, 3)

A method for inhibiting the growth of cells expressing human CD40 antigen, comprising administering the antibody or antigen-binding fragment of any one of claims 1-3 to the cells, which antibody or antigen-binding fragment specifically binds to the human cell surface CD40 antigen, wherein the binding of the antibody or antigen-binding fragment to the CD40 antigen inhibits the growth or differentiation of the cells.

### Claim 32 (depends on 1, 2, 3)

A method for treating a subject having a CD40-associated disorder, comprising administering to the subject the antibody or antigen-binding fragment of any one of claims 1-3, which antibody or antigen-binding fragment specifically binds to human CD40, wherein the binding of the antibody or antigen-binding fragment to CD40 inhibits the growth or differentiation of cells of the CD40-associated disorder.

### Claim 33 (depends on 32)

The method of claim 32, wherein the cells of the CD40-associated disorder are B lymphoblastoid cells, pancreatic, lung cells, breast cells, ovarian cells, colon cells, prostate cells, skin cells, head and neck cells, bladder cells, bone cells or kidney cells.

### Claim 34 (depends on 32)

The method of claim 32, wherein the CD40-associated disorder is chronic lymphocytic leukemia, Burkitt's lymphoma, multiple myeloma, a T cell lymphoma, Non-Hodgkin's Lymphoma, Hodgkin's Disease, Waldenstrom's macroglobulinemia or Kaposi's sarcoma.

### Claim 35 (depends on 1, 2, 3)

A method for inducing depletion of peripheral B cells, comprising administering to the cells the antibody or antigen-binding fragment of any one of claims 1-3, which antibody or antigen-binding fragment specifically binds to a human cell surface CD40 antigen, wherein the binding of the antibody or antigen-binding fragment to the CD40 antigen induces depletion of the cells.

### Claim 36 (depends on 35)

The method of claim 35, wherein the antibody or antigen-binding fragment is administered to a subject having an immune disorder.

### Claim 37 (depends on 36)

The method of claim 36, wherein the immune disorder is rheumatoid arthritis or systemic lupus erythematosus.

### Claim 38 (depends on 1, 2, 3)

The antibody or antigen-binding fragment of any one of claims 1-3, wherein the antibody or antigen-binding fragment competes for binding with monoclonal antibody S2C6 that is secreted by a hybridoma having ATCC Accession No. PTA-110.

### Claim 39 (depends on 1, 2, 3)

A pharmaceutical composition comprising:
(i) the antibody or antigen-binding fragment of any one of claims 1-3; and
(ii) a pharmaceutically acceptable excipient.

### Claim 40 (depends on 1)

An isolated polynucleotide encoding the humanized heavy chain variable region of the antibody or antigen-binding fragment of claim 1.

### Claim 41 (depends on 2)

An isolated polynucleotide encoding the humanized light chain variable region of the antibody or antigen-binding fragment of claim 2.

### Claim 42 (depends on 40)

The isolated polynucleotide of claim 40, further encoding a humanized light chain variable region comprising a framework region comprising an amino acid sequence at least 90% identical to the framework region of the human variable region light chain subgroup kappa I concensus amino acid sequence of SEQ ID NO:13 and comprising at least one CDR having an amino acid sequence at least 90% identical to a corresponding heavy chain CDR of SEQ ID NO:3.

### Claim 43 (depends on 40, 42)

The isolated polynucleotide of claim 40 or 42, wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, or SEQ ID NO:11.

### Claim 44 (depends on 41, 42)

The isolated polynucleotide of claim 41 or 42, wherein the polynucleotide encodes the light chain variable domain amino acid sequence of SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:16.

### Claim 45 (depends on 43)

The isolated polynucleotide of claim 43, wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence of SEQ ID NO:3 and SEQ ID NO:14, respectively; SEQ ID NO:4 and SEQ ID NO:14, respectively; SEQ ID NO:5 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:14, respectively; SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:8 and SEQ ID NO:14, respectively; SEQ ID NO:9 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:15, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:7 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:14, respectively; SEQ ID NO:11 and SEQ ID NO:14, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO:11 and SEQ ID NO:16, respectively.

### Claim 46 (depends on 43)

The isolated polynucleotide of claim 43, wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence of SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:7 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:14, respectively; SEQ ID NO:11 and SEQ ID NO:14, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO: 11 and SEQ ID NO:16, respectively.

### Claim 47 (depends on 43)

The isolated polynucleotide of claim 43, wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence SEQ ID NO:7 and SEQ ID NO:14, respectively; SEQ ID NO:6 and SEQ ID NO:16, respectively; SEQ ID NO:10 and SEQ ID NO:16, respectively; or SEQ ID NO: 11 and SEQ ID NO:16, respectively.

### Claim 48 (depends on 43)

The isolated polynucleotide of claim 43, wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence of SEQ ID NO:3 and SEQ ID NO:14, respectively.

### Claim 49 (depends on 43)

The isolated polynucleotide of claim 43, wherein the polynucleotide encodes the heavy chain variable domain amino acid sequence and the light chain variable domain amino acid sequence of SEQ ID NO:10 and SEQ ID NO:16, respectively.