Use of antagonist anti-cd40 antibodies for treatment of chronic lymphocytic leukemia

A multiple myeloma, monoclonal antibody technology, applied in the direction of antibody medical components, antibodies, anti-tumor drugs, etc., can solve the problems of multi-drug resistance limitation, low cell proliferation rate, etc.

Inactive Publication Date: 2007-01-24
CHIRON CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Low cell proliferation rates and development of multidrug resistance limit the efficacy of all available chemotherapy regimens for MM

Method used

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  • Use of antagonist anti-cd40 antibodies for treatment of chronic lymphocytic leukemia
  • Use of antagonist anti-cd40 antibodies for treatment of chronic lymphocytic leukemia
  • Use of antagonist anti-cd40 antibodies for treatment of chronic lymphocytic leukemia

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0093] The art provides basic guidance regarding the preparation and use of polypeptide variants. In preparing anti-CD40 antibody variants, one skilled in the art can readily determine which modifications to the nucleotide or amino acid sequence of the native protein will result in a protein suitable for use as a therapeutically active ingredient in the pharmaceutical composition of the methods of the invention. Variants.

[0094] Methods of Therapy Using Antagonist Anti-CD40 Antibodies of the Invention

[0095] The methods of the invention involve treating a subject (ie, patient) with multiple myeloma, wherein cells of the cancer express the CD40 antigen, with an antagonist anti-CD40 antibody. "CD40-expressing multiple myeloma cells" refers to multiple myeloma cells expressing the CD40 antigen. Successful treatment of multiple myeloma depends on the stage of the cancer at the time of diagnosis and whether the subject has previously or will be receiving other therapies in co...

Embodiment 1

[0167] Example 1: mAb 5.9 and CHIR-12.12 and CD40 in MM patients + Multiple Myeloma (MM) Cell Binding

[0168] Multiple myeloma (MM) cells were stained with FITC-labeled anti-CD40 mAb 5.9 and CHIR-12.12 and control FITC-labeled human IgG1. CD40 from 8 patients + MM cells were incubated with FITC-labeled anti-CD40 mAb 5.9 or CHIR-12.12 or FITC-labeled human IgG1. Flow cytometric analysis was performed with FACSCAN V (Becton Dickinson, San Jose, California).

Embodiment 2

[0169] Example 2: Anti-CD40 mAb 5.9 and CHIR-12.12 block CD40 ligand-mediated survival signaling in multiple myeloma (MM) cells

[0170] Antibody concentration (μg / ml)

MM cells

MM cells plus express CD40-

Ligand immobilization in CHO cells

0

+

-

0

+

+

1.0 (anti-CD40)

+

+

10.0 (anti-CD40)

+

+

100.0 (anti-CD40)

+

+

1.0 (control IgG1)

+

+

10.0 (control IgG1)

+

+

100.0 (control IgG1)

+

+

[0171] After 72 h the cultures were analyzed as follows:

[0172] Viable cells were counted and cell death determined by PI and Annexine V staining

[0173] Proliferation was measured by overnight pulse with tritiated thymidine

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Abstract

Methods of therapy for treating a subject for multiple myeloma are provided. The methods comprise administering a therapeutically effective amount of an antagonist anti-CD40 antibody or antigen-binding fragment thereof to a patient in need thereof. The antagonist anti-CD40 antibody or antigen-binding fragment thereof is free of significant agonist activity, but exhibits antagonist activity when the antibody binds a CD40 antigen on a human CD40-expressing cell. Antagonist activity of the anti- antibody or antigen-binding fragment thereof beneficially inhibits proliferation and / or differentiation of human CD40 expressing multiple myeloma cells.

Description

field of invention [0001] The present invention relates to methods of treating multiple myeloma using antagonistic anti-CD40 monoclonal antibodies. Background of the invention [0002] Multiple myeloma (MM) is a B-cell malignancy characterized by the underlying accumulation in the bone marrow of secretory plasma cells with low proliferative index and prolonged life span. The disease eventually attacks the bone or bone marrow, causing multiple tumors and lesions throughout the skeletal system. Multiple myeloma is responsible for approximately 1% of all cancers and slightly over 10% of all hematological malignancies. MM increases in incidence in the elderly population, with the median age at diagnosis being approximately 61 years. Current treatment regimens, which include combinations of chemotherapy drugs such as vincristine, BCNU, melphalan, cyclophosphamide, doxorubicin, and prednisone or dexamethasone, produce a complete regression rate of only...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61P35/02C07K16/28
CPCA61K39/39558C07K2317/34C07K2317/21A61K2039/505C07K16/2878A61K38/2013C07K2316/96C07K2317/732C07K2317/73C07K2317/76A61P35/00A61P35/02A61K2300/00A61K39/395C07K16/28
Inventor L·隆M·卢克曼A·亚巴娜发I·扎罗
Owner CHIRON CORP
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