# US 2019/0169301 A1 · Anti-cd40 antibodies

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- Number: US 2019/0169301 A1
- Document ID: US20190169301A1
- Status: Published application
- Kind: A1
- Application number: 16/031,209
- Filed: 2018-07-10
- Published: 2019-06-06
- Earliest claimed: 2010-03-31
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Boehringer Ingelheim International GmbH
- Inventors: Rachel Rebecca Barrett; Scott Ronald Brodeur; Keith Canada; Tobias Litzenburger; Sanjaya Singh
- Web page: https://patentgrep.com/patent/US20190169301A1

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/12: for climacteric disorders
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/00: Drugs for disorders of the senses
- 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 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 39/00: General protective or antinoxious agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 1/22: Affinity chromatography or related techniques based upon selective absorption processes
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/53: Hinge
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/71: Decreased effector function due to an Fc-modification
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to new humanized antagonistic anti-CD40 antibodies and therapeutic and diagnostic methods and compositions for using the same.

## Claims

### Claim at position 1

1-4. (canceled)

### Claim 5

A humanized antibody, wherein said antibody comprises a heavy chain and a light chain, wherein the heavy chain sequence and light chain sequence are selected from the group consisting of:
a) a heavy chain CDR1 sequence selected from the group consisting of SEQ ID NO: 9 through SEQ ID NO:11, a heavy chain CDR2 sequence selected from the group consisting of SEQ ID NO:12 through SEQ ID NO:15, and a heavy chain CDR3 sequence selected from the group consisting of SEQ ID NO:16 through SEQ ID NO:17; and
b) the light chain CDR1 sequence has a sequence selected from the group consisting of SEQ ID NO:18 through SEQ ID NO:21, a light chain CDR2 sequence of SEQ ID NO:22 through SEQ ID NO:23, and a light chain CDR3 sequence selected from the group consisting of SEQ ID NO:24 through SEQ ID NO:25.

### Claim 6 (depends on 5)

The antibody of claim 5, wherein said antibody comprises a heavy chain CDR1 sequence of SEQ ID NO: 10, a heavy chain CDR2 sequence of SEQ ID NO:13 and a heavy chain CDR3 sequence of SEQ ID NO:16; and wherein said antibody comprises a light chain CDR1 sequence of SEQ ID NO:19, a light chain CDR2 sequence of SEQ ID NO:22 and a light chain CDR3 sequence of SEQ ID NO:24.

### Claim 7 (depends on 5)

The antibody of claim 5, wherein said antibody comprises a heavy chain CDR1 sequence of SEQ ID NO: 9, a heavy chain CDR2 sequence of SEQ ID NO:14 and a heavy chain CDR3 sequence of SEQ ID NO:16; and wherein said antibody comprises a light chain CDR1 sequence of SEQ ID NO:20, a light chain CDR2 sequence of SEQ ID NO:22 and a light chain CDR3 sequence of SEQ ID NO:24.

### Claim 8 (depends on 5)

The antibody of claim 5, wherein said antibody comprises a heavy chain CDR1 sequence of SEQ ID NO: 11, a heavy chain CDR2 sequence of SEQ ID NO:15 and a heavy chain CDR3 sequence of SEQ ID NO:17; and wherein said antibody comprises a light chain CDR1 sequence of SEQ ID NO:21, a light chain CDR2 sequence of SEQ ID NO:23 and a light chain CDR3 sequence of SEQ ID NO:25.

### Claim 9

A humanized monoclonal antibody or antibody fragment having a heavy chain variable domain and a light chain variable region comprising the amino acid sequences of SEQ ID NO:27 and SEQ ID NO:26, respectively; SEQ ID NO:28 and SEQ ID NO:26, respectively; SEQ ID NO:29 and SEQ ID NO:26, respectively; SEQ ID NO:30 and SEQ ID NO:26, respectively; SEQ ID NO:32 and SEQ ID NO:31, respectively; SEQ ID NO:33 and SEQ ID NO:31, respectively; SEQ ID NO:34 and SEQ ID NO:31, respectively; SEQ ID NO:35 and SEQ ID NO:31, respectively; SEQ ID NO:37 and SEQ ID NO:36, respectively; SEQ ID NO:38 and SEQ ID NO:36, respectively; SEQ ID NO:39 and SEQ ID NO:36, respectively; SEQ ID NO:40 and SEQ ID NO: 36, respectively.

### Claim 10

An isolated antibody or antigen-binding fragment that specifically binds to human CD40, comprising:
a) 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 amino acid sequence of SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34 or SEQ ID NO:35, and comprising a light chain amino acid sequence at least 90% identical to a corresponding light chain variable sequence of SEQ ID NO:31; or
b) 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 amino acid sequence of SEQ ID NO: 37, SEQ ID NO:38; SEQ ID NO:39 or SEQ ID NO: 40, and comprising a light chain amino acid sequence at least 90% identical to a corresponding light chain sequence of SEQ ID NO:36.

### Claim 11

A humanized monoclonal antibody or antigen binding fragment of an antibody wherein said antibody or antigen binding fragment of the antibody specifically binds to human CD40 having an antagonistic activity IC50 of less than 1 nM and has no agonism up to 100 μg/ml in B cell proliferation and wherein said antibody or antigen binding fragment of the antibody is further characterized in that the antibody or antigen binding fragment of the antibody has an in vivo half-life in non-human primates that is at least 10 days; and wherein said antibody or antigen binding fragment of the antibody optionally has a half-life in cynomolgus monkeys of greater than 8 days at a dose of less than 30 mg/kg.

### Claim 12 (depends on 5)

A method of blocking the function of human CD40 in a mammal comprising administering to said mammal a composition comprising an antibody of claim 5 in an amount sufficient to block a CD40 mediated immune response in said mammal.

### Claim 13 (depends on 5)

A method of treating or ameliorating a disease or disorder in a mammal comprising administering to said mammal a composition comprising an antibody of claim 5 in an amount sufficient to decrease one or more of the symptoms of the disease or disorder in the mammal.

### Claim 14 (depends on 13)

The method of claim 13, wherein the disease or disorder is selected from the group consisting of: graft versus host disease, autoimmune or inflammatory disease, and CD40-related disorder.

### Claim 15 (depends on 14)

The method of claim 14, wherein the autoimmune or inflammatory disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, proliferative lupus glomerulonephritis, inflammatory bowel disease (IBD), psoriasis, idiopathic thrombocytopenic purpura (ITP), Crohn's Disease and systemic lupus erythematosus (SLE), Hashimoto's thyroiditis, primary myxoedema, thyrotoxicosis/Graves disease, pernicious anaemia, autoimmune atrophic gastritis, autoimmune carditis, Addison's disease, premature menopause, type 1-diabetes mellitus, Good pasture's syndrome, myasthenia gravis, autoimmune haemolytic anaemia, idiopathic leucopenia, primary biliary cirrhosis, active chronic hepatitis (HBs Ag negative), cryptogenic cirrhosis, Sjogren's syndrome, dermatomyositis, scleroderma, mixed tissues connective disease, discoid lupus erythematosus, and systemic vasculitis.

### Claim 16 (depends on 13)

The method of claim 13, further comprising administering a second therapeutic agent selected.

### Claim 17 (depends on 13)

The method of claim 13, wherein said antibody is administered by a parenteral route, intravenous route or subcutaneous route of administration.

### Claim 18 (depends on 5)

A pharmaceutical composition comprising: (i) the antibody of claim 5; and (ii) a pharmaceutically acceptable excipient; and wherein the antibody or antigen binding fragment thereof is optionally conjugated to a second agent.

### Claim 19

An isolated polynucleotide encoding a heavy chain variable region amino acid sequence or a light chain variable region, wherein the heavy chain variable region amino acid sequence comprises any of SEQ ID NO: 1 to 4, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO: 29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID. NO. 50, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73; and light chain variable region amino acid sequence comprises any of SEQ ID NO: 5 to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:74, SEQ ID NO:75, or SEQ ID NO:76.

### Claim 20

A humanized monoclonal antibody or antigen binding fragment comprising a heavy chain domain that is at least 90% identical to the amino acid sequence of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, and a light chain domain that is at least 90% identical to the amino acid sequence of SEQ ID NO:26, SEQ ID NO:31 or SEQ ID NO:36.

### Claim 21

A humanized monoclonal antibody or antigen binding fragment comprising a heavy chain domain that is at least 95% identical to the amino acid sequence of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, and a light chain domain that is at least 90% identical to the amino acid sequence of SEQ ID NO:26, SEQ ID NO:31 or SEQ ID NO:36.

### Claim 22

A humanized monoclonal antibody or antigen binding fragment comprising a heavy chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 to 4, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73, and a light chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5 to SEQ ID NO:8, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:74, SEQ ID NO:75, or SEQ ID NO:76.

### Claim 23

An isolated anti-CD40 antibody that binds the same epitope on CD40 as an antibody comprising a heavy chain domain that comprises the amino acid sequence of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39 or SEQ ID NO:40, and a light chain domain that comprises the amino acid sequence of SEQ ID NO:26, SEQ ID NO:31 or SEQ ID NO:36.

### Claim 24 (depends on 23)

The isolated anti-CD40 antibody of claim 23, wherein the antibody comprises a heavy chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 to 4, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO: 29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73, and a light chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5 to SEQ ID NO:8, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:36, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:74, SEQ ID NO:75, or SEQ ID NO:76.

### Claim 25 (depends on 20)

The antibody or antigen binding fragment of claim 20, wherein the antibody or antigen binding fragment of the antibody specifically binds to human CD40; has an antagonistic activity IC50 of less than 1 nM; or has no agonism up to 100 μg/ml in B cell proliferation.

### Claim 26 (depends on 20)

The antibody or antigen binding fragment of claim 20, wherein the antibody or antigen binding fragment of the antibody has an in vivo half-life in non-human primates that is at least 10 days or has a half-life in cynomolgus monkeys of greater than 8 days at a dose of less than 30 mg/kg.

### Claim 27 (depends on 20)

The antibody or antigen binding fragment of claim 20, wherein the antibody or antigen binding fragment inhibits the growth or differentiation of cells of the CD40-associated disorder.

### Claim 28 (depends on 20)

The antibody or antigen binding fragment of claim 20, wherein the antibody or antigen binding fragment does not stimulate production of cytokines from B cells in the absence of CD40L.

### Claim 29 (depends on 20)

The antibody or antigen binding fragment of claim 20, wherein the antibody or antigen binding fragment inhibits production of cytokines from B cells in the absence of CD40L.

### Claim 30 (depends on 20)

The antibody or antigen binding fragment of claim 20, wherein the antibody or antigen binding fragment binds to human CD40 in the presence of 50% human serum with a reduction of on rate less than two fold.

### Claim 31 (depends on 20)

A method of blocking the function of human CD40 in a mammal comprising administering to said mammal a composition comprising an antibody according to claim 20 in an amount sufficient to block a CD40 mediated immune response in said mammal.

### Claim 32 (depends on 20)

A method of treating or ameliorating a disease or disorder in a mammal comprising administering to said mammal a composition comprising an antibody according to claim 20 in an amount sufficient to decrease one or more of the symptoms of the disease or disorder in the mammal.

### Claim 33 (depends on 32)

The method of claim 32, wherein the disease or disorder is selected from the group consisting of: graft versus host disease, autoimmune or inflammatory disease, and CD40-related disorder.

### Claim 34 (depends on 33)

The method of claim 33, wherein the autoimmune or inflammatory disease is selected from the group consisting of lupus nephritis, rheumatoid arthritis, multiple sclerosis, proliferative lupus glomerulonephritis, inflammatory bowel disease (IBD), psoriasis, idiopathic thrombocytopenic purpura (ITP), Crohn's Disease and systemic lupus erythematosus (SLE), Hashimoto's thyroiditis, primary myxoedema, thyrotoxicosis/Graves disease, pernicious anaemia, autoimmune atrophic gastritis, autoimmune carditis, Addison's disease, premature menopause, type 1-diabetes mellitus, Good pasture's syndrome, myasthenia gravis, autoimmune haemolytic anaemia, idiopathic leucopenia, primary biliary cirrhosis, active chronic hepatitis (HBs Ag negative), cryptogenic cirrhosis, Sjogren's syndrome, dermatomyositis, scleroderma, mixed tissues connective disease, discoid lupus erythematosus, and systemic vasculitis.

### Claim 35

An isolated polynucleotide encoding an antibody or antigen binding fragment comprising a heavy chain domain that is at least 90% identical to the amino acid sequence of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, and a light chain domain that is at least 90% identical to the amino acid sequence of SEQ ID NO:26, SEQ ID NO:31 or SEQ ID NO:36.

### Claim 36

An isolated polynucleotide encoding an antibody or antigen binding fragment comprising a heavy chain domain that is at least 95% identical to the amino acid sequence of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40, and a light chain domain that is at least 90% identical to the amino acid sequence of SEQ ID NO:26, SEQ ID NO:31 or SEQ ID NO:36.

### Claim 37

An isolated polynucleotide encoding an antibody or antigen binding fragment comprising a heavy chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 to 4, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73, and a light chain variable domain that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5 to SEQ ID NO:8, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:74, SEQ ID NO:75, or SEQ ID NO:76.

### Claim 38 (depends on 35)

The isolated polynucleotide of claim 35, wherein the antibody or antigen binding fragment encoded by the polynucleotide specifically binds to human CD40; has an antagonistic activity IC50 of less than 1 nM; or has no agonism up to 100 μg/ml in B cell proliferation.

### Claim 39 (depends on 35)

The isolated polynucleotide of claim 35, wherein the antibody or antigen binding fragment encoded by the polynucleotide has an in vivo half-life in non-human primates that is at least 10 days or has a half-life in cynomolgus monkeys of greater than 8 days at a dose of less than 30 mg/kg.

### Claim 40 (depends on 35)

The isolated polynucleotide of claim 35, wherein the antibody or antigen binding fragment encoded by the polynucleotide inhibits the growth or differentiation of cells of the CD40-associated disorder.

### Claim 41 (depends on 35)

The isolated polynucleotide of claim 35, wherein the antibody or antigen binding fragment encoded by the polynucleotide does not stimulate production of cytokines from B cells in the absence of CD40L.

### Claim 42 (depends on 35)

The isolated polynucleotide of claim 35, wherein the antibody or antigen binding fragment encoded by the polynucleotide inhibits production of cytokines from B cells in the absence of CD40L.

### Claim 43 (depends on 35)

The isolated polynucleotide of claim 35, wherein the antibody or antigen binding fragment encoded by the polynucleotide binds to human CD40 in the presence of 50% human serum with a reduction of on rate less than two fold.

### Claim 44 (depends on 35)

A method of making an antibody or antigen binding fragment thereof comprising expressing the polynucleotide of claim 35 in a recombinant host cell culture.

### Claim 45 (depends on 44)

The method of claim 44, wherein the host cell is a mammalian host cell.

### Claim 46 (depends on 45)

The method of claim 45, wherein the mammalian host cell is selected from the group consisting of a human embryonic kidney line, a baby hamster kidney cell (BHK), a Chinese hamster ovary cells/-DHFR1 (CHO), a mouse sertoli cell, a monkey kidney cells, an African green monkey kidney cell, a human cervical carcinoma cell, a canine kidney cell, a buffalo rat liver cell, a human lung cell, a human liver cell, a mouse mammary tumor cell, a TR1 cell, a MRC 5 cell, a FS4 cell, and a human hepatoma cell.

### Claim 47 (depends on 35)

A vector comprising the polynucleotide of claim 35.

### Claim 48 (depends on 47)

The vector of claim 47 further comprising at least one of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, or a transcription termination sequence.

### Claim 49 (depends on 47)

The vector of claim 47, wherein the vector is suitable for expression in a mammalian host cell.

### Claim 50 (depends on 35)

A method of treating or ameliorating a disease or disorder in a mammal comprising administering to said mammal a composition comprising an antibody or an antigen fragment encoded by the polynucleotide of claim 35 in an amount sufficient to decrease one or more of the symptoms of the disease or disorder in the mammal.

### Claim 51 (depends on 50)

The method of claim 50, wherein the disease or disorder is selected from the group consisting of: graft versus host disease, autoimmune or inflammatory disease, and CD40-related disorder.

### Claim 52 (depends on 51)

The method of claim 51, wherein the autoimmune or inflammatory disease is selected from the group consisting of lupus nephritis, rheumatoid arthritis, multiple sclerosis, proliferative lupus glomerulonephritis, inflammatory bowel disease (IBD), psoriasis, idiopathic thrombocytopenic purpura (ITP), Crohn's Disease and systemic lupus erythematosus (SLE), Hashimoto's thyroiditis, primary myxoedema, thyrotoxicosis/Graves disease, pernicious anaemia, autoimmune atrophic gastritis, autoimmune carditis, Addison's disease, premature menopause, type 1-diabetes mellitus, Good pasture's syndrome, myasthenia gravis, autoimmune haemolytic anaemia, idiopathic leucopenia, primary biliary cirrhosis, active chronic hepatitis (HBs Ag negative), cryptogenic cirrhosis, Sjogren's syndrome, dermatomyositis, scleroderma, mixed tissues connective disease, discoid lupus erythematosus, and systemic vasculitis.