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Pharmaceutical compositions directed to erb-b1 receptors

A bispecific antibody and antibody technology, applied in the direction of antibody, anti-animal/human immunoglobulin, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc.

Inactive Publication Date: 2005-11-30
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Although there are some promising drugs and methods for the treatment of tumors under development and marketing, there is still a need for other agents and pharmaceutical compositions and combinations with improved properties and increased efficacy

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0222] Preparation of F(AB')2-fragments of MAB 425 and MAB 225

[0223] Anti-EGFR antibody humanized MAb 425 and chimeric MAb 225 were converted to F(ab')2 fragments using limited proteolysis. The production of F(ab')2 antibodies must be optimized for each antibody. The general protocol for this preparation is as follows.

[0224] Pepsin cleavage was optimal for both antibodies, however papain cleavage was also suitable. Residual intact antibody and Fc fragments were removed from the protein A sepharose column. The yield of F(ab')2 fragment was close to 100%. F(ab')2 fragments can be stored at -20°C without losing any activity for a long time.

[0225] General scheme:

[0226] Growth and fermentation→centrifugation→ultrafiltration→protein A chromatography→dialysis / ultrafiltration→cracking→protein A chromatography→dialysis / ultrafiltration→F(ab’)2 product

[0227] details:

[0228] PBS, pH: 7.4

[0229] Protein content: 5.06 mg / ml (Pierce).

[0230...

Embodiment 2

[0246] Example 2: Preparation of bispecific antibody BAB

[0247] Bispecific antibodies were produced by chemical recombination of IgG fragments using the method described by Brennan et al. (Science, 1985, 229, 81-83). Each step of the modification method of the present invention is as follows:

[0248] F(ab′)2 product→reduction to Fab′→gel chromatography→derivatization→gel chromatography→conjugation→gel chromatography→ultrafiltration→sterile filtration→BAbs

[0249] Both specific F(ab')2 fragments were converted to Fab'. The success of the conjugation step depends on the selection of an appropriate Fab' fragment for Ellmann's modification. For BAbs derived from MAb 225 / MAb 425, the component was modified. After introducing these modifications, the yield of individual BAbs was 20-30%. Anti-225 Fab' was modified with Ellman's reagent and conjugated to 425 specific Fab'. Bispecific antibodies were recovered by gel filtration.

[0250] details:

[0251] In ...

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PUM

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Abstract

The invention relates to novel bispecific antibodies and their use in tumor therapy. The novel antibodies have the ability to bind to ErbB receptors, preferably ErbB1 receptors, which are overexpressed on many cancer tissues. Since the different specificities of the antigen-binding sites are directed to different epitopes within the binding domain of same or different ErbB receptors, these antibodies are more effective with respect to inhibition and down-regulation of the ErbB receptor and the corresponding signaling cascade.

Description

field of invention [0001] The present invention relates to novel bispecific antibodies and their use in tumor therapy. The novel antibody can bind to ErbB receptors overexpressed on various cancer tissues, especially ErbB1 receptors. Because the different specificities of the antigen binding site target different epitopes within the binding domains of the same or different ErbB receptors, these antibodies are more effective at inhibiting and downregulating ErbB receptors and corresponding signaling cascades. The present invention also relates to pharmaceutical compositions comprising said bispecific antibody or fragment thereof and other pharmaceutically effective agents such as monospecific antibodies, immunoconjugates and / or cytotoxic agents. Background of the invention [0002] For more than 20 years, biomolecules, such as monoclonal antibodies (MAbs) or other proteins / polypeptides, and small chemical compounds directed against various receptors and other antigens on the...

Claims

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Application Information

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IPC IPC(8): A61K39/395
Inventor H－G・克赖施
Owner MERCK PATENT GMBH
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