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Uses of anti-CD40 antibodies
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A technology of antibody and monoclonal antibody, applied in the application field of anti-CD40 antibody, can solve the problem of wasting patients
Inactive Publication Date: 2009-01-21
NOVARTIS AG +1
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Moreover, rituximab can deplete normal B cells in patients
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preparation example Construction
[0191] Basic guidelines for the preparation and use of polypeptide variants are provided in the art. In preparing variants of anti-CD40 antibodies, one skilled in the art will readily determine which modifications to the nucleotide or amino acid sequence of the native protein will result in a therapeutically active ingredient suitable for use in the pharmaceutical compositions of the methods of the invention variant of .
[0192] The anti-CD40 antibody used in the method of the present invention preferably has at least one of the following biological activities in vitro and / or in vivo: inhibition of T cell-stimulated normal human peripheral B cells to secrete immunoglobulin; inhibition of CD40L expressing cells or soluble CD40 ligand ( sCD40L)-stimulated survival and / or proliferation of normal human peripheral B cells; inhibition of Jurkat T-cell-stimulated normal human peripheral B cell survival and / or proliferation; inhibition of sCD40L or solid-phase CD40L-stimulated any ce...
Embodiment 1
[0295] Example 1: Analysis of ADCC of Cell Lines
[0296] The relative ADCC activities of CHIR-12.12 and rituximab were compared against various malignant B cell lines expressing both CD40 and CD20 antigens, including lymphoma cell lines (Daudi, Namar cell lines), multiple Myeloma cell lines (ARH77, IM-9), B-ALL cell line (CCRF-SB) and B-CLL cell line (EHEB).
[0297] Determination of percent maximum lysis and ED, respectively 50 , comparing the ADCC potency and strength of CHIR-12.12 and rituximab. The results of these trials can be found in Figure 1A -1F. In all target cell lines, CHIR-12.12 was a more potent and potent mediator of ADCC compared to rituximab. In the six cell lines examined, the number of CD20 molecules per cell surface was 2.6-30.8 times higher than the number of CD40 molecules. These data demonstrate that CHIR-12.12 lyses malignant B-cell lines more efficiently than rituximab, despite displaying fewer CD40 molecules compared to CD20.
Embodiment 2
[0298] Example 2: Analysis of ADCC in CLL patient cells
[0299] The relative ADCC activities of CHIR-12.12 and rituximab on ex vivo primary CLL cells from 8 patients were compared. Compared to rituximab, CHIR-12.12 had higher ADCC activity against CLL in all patients (see Figures 2A-D and Figure 3). The results are shown in Figure 3. CHIR-12.12 was more potent than rituximab.
[0301] Target cells: CLL patient cells, 5000 cells / well. Effector cells: purified normal human NK cells, 50,000 cells / well. E:T ratio: 10. Antibody concentrations: 0.00001, 0.0001, 0.001, 0.01, 0.1, 1 and 10 μg / ml. Incubation time: 4 hours. Medium: RPMI (without phenol red) + 10% FBS + 1% P / S. Culture device: 96-well round bottom plate. Readout: Released Calcein fluorescence AM was measured in Arbitrary Fluorescence Units (AFU) with excitation at 485 nm / emission at 535 nm. Calculation: % specific lysis=100×(AFU detection value-AFU...
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Abstract
Methods for treating a human patient for an inflammatory or autoimmune disease that is associated with CD40-expressing cells are provided, where the human patient is heterozygous or homozygous for FcGammaRIIIa-158F (genotype V / F or F / F). Also provided are methods of inhibiting antibody production by B cells in a human patient who is heterozygous or homozygous for FcGammaRIIIa-158F (genotype V / F or F / F). The methods comprise administering to the human patient a therapeutically or prophylactically effective amount of an anti-CD40 antibody. Methods and kits for identifying a human patient with an inflammatory or autoimmune disease that is treatable with an anti-CD40 antibody and which is non-responsive or refractory to treatment with rituximab (Rituxan TM ), as well as methods and kits for selecting an antibody therapy for treatment of a human patient having an inflammatory or autoimmune disease that is non-responsive or refractory to treatment with rituximab (Rituxan TM ), are also provided. The methods of the present invention find use in treatment of inflammatory diseases and autoimmune diseases that are associated with CD40-expressing cells. These methods are particularly advantageous with respect to inflammatory diseases and autoimmune diseases that are associated with cells expressing both CD40 and CD20, as the methods enable the treatment of patients having an inflammatory or autoimmune disease that is non-responsive or refractory to therapy with other therapeutic agents such as anti-CD20 antibodies.
Description
[0001] The present invention relates to new applications of anti-CD40 antibodies, in particular to the treatment of inflammatory diseases and autoimmune diseases in which cells express CD40. Background of the Invention [0002] Many ligand members of the tumor necrosis factor (TNF) family and their corresponding receptors can regulate the growth of normal cells by inducing apoptosis or enhancing cell survival and proliferation. This balance between apoptotic signals and survival and proliferation signals maintains normal cellular homeostasis. To date, at least 26 TNF family receptors and 18 TNF family ligands have been identified. The biologically active forms of these receptors and ligands are self-assembled protein trimers. Transmembrane and soluble forms of these receptors and ligands have been identified. Although the intracellular domains of these receptors have no sequence homology, their extracellular domains contain 40 amino acid, cysteine-rich repeats. Their cytopl...
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