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Anti-vegf antibodies and their uses

An antibody and bevacizumab technology, applied in the direction of antibodies, applications, anti-inflammatory agents, etc., can solve the problems of reducing the treatment benefits of patients and limiting antibody re-administration

Inactive Publication Date: 2012-05-30
ABBVIE BIOTHERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Also, although bevacizumab is a humanized antibody, it elicits an immune response when administered to humans
Such an immune response can lead to immune complex-mediated clearance of the antibody or fragment from circulation and make repeated administration unsuitable for therapy, thereby reducing the therapeutic benefit to the patient and limiting re-administration of the antibody

Method used

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  • Anti-vegf antibodies and their uses
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  • Anti-vegf antibodies and their uses

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0226] 7. Example 1: Identification of T cell epitopes of bevacizumab

[0227] 7.1 Materials and methods

[0228] 7.1.1 Peptides

[0229] Peptides were synthesized from Mimotope (Adelaide, Australia) using a multi-pin format. The sequences of the bevacizumab light and heavy chain V regions were synthesized in the form of 15 peptides overlapping by 12 amino acids (Tables 3 and 4), for a total of 69 peptides. Peptides were lyophilized and resuspended in DMSO (Sigma-Aldrich) at approximately 1 mg / mL to 2 mg / mL. Stock peptides were stored frozen at -20°C.

[0230] 7.1.2 Human peripheral blood mononuclear cells

[0231] Community donor buffy coat product was purchased from Stanford Blood Center (Palo Alto, CA). The buffy coat material was diluted 1:1 by volume with DPBS without calcium or magnesium. Dilute the buffy coat material (25ml to 35ml) with 12.5ml of FicollPaque-PLUS (GE Healthcare) in a 50ml conical centrifuge tube (Sarsted or Coase The lower layer of the tower (...

example 2

[0245] 8. Example 2: Identification of bevacizumab variants with increased affinity for VEGF

[0246] A comprehensive mutational analysis of the bevacizumab antibody was performed to identify mutants with increased affinity for VEGF compared to bevacizumab. Candidate high-affinity mutants were analyzed by BIAcore to confirm their binding characteristics: increased affinity for VEGF compared to bevacizumab.

[0247] 8.1 Materials and methods

[0248] 8.1.1 BIAcore

[0249] Fifteen variant bevacizumab VH region constructs were cloned together with the unmodified VL region into human IgG containing 1 The plasmid was expressed in 293T / 17 cell line by transient transfection, and the antibody was purified by protein A or protein G affinity method. Antibody responses to VEGF (R&D systems, Minneapolis, Minnesota) were determined by using BIAcore 2000 and 3000 surface plasmon resonance systems (BIAcore; GE Healthcare, Piscataway, NJ). Adams (Minneapolis, MN)) affinity. Polymer w...

example 3

[0253] 9. Example 3: Selection of Deimmunized Variant Peptides

[0254] Variant peptides (Tables 14 to 16) corresponding to the immunogenic regions of bevacizumab (see Example 1) were generated. Variant peptides were selected according to the comprehensive mutational analysis described in Example 2, in which CDR modifications were identified that did not substantially reduce the binding affinity of bevacizumab for VEGF.

[0255] A total of 77 peptides were synthesized and tested based on antigen binding studies, including two syntheses of each parental 15 peptides. A total of 93 donors were tested with the parental and variant peptides using the method described in Section 7.1 and the results are shown in Figure 4A to Figure 4C middle. Specifically, Figure 4A to Figure 4C Demonstration of CD4+ T cell responses to mutant bevacizumab epitope peptides. The average response to the unmodified parental epitope sequence is indicated by open markers. Large circles indicate se...

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Abstract

The present disclosure relates to antibodies directed to vascular endothelial growth factor (VEGF) and uses of such antibodies, for example to treat diseases associated with the activity and / or overproduction of VEGF.

Description

[0001] Cross References and Sequence Listings to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 61 / 218,005, filed June 17, 2009, under 35 U.S.C. § 119(e), the contents of which are hereby incorporated by reference in their entirety. [0003] This application contains a Sequence Listing, which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 15, 2010, is named 381493PC.txt and is 141,482 bytes in size. technical field [0004] The present invention relates to anti-VEGF antibodies, pharmaceutical compositions comprising anti-VEGF antibodies and therapeutic uses of these antibodies. Background technique [0005] Angiogenesis is an attractive therapeutic target due to its involvement in a variety of pathological conditions, including tumor growth, proliferative retinopathy, age-related macular degeneration, rheumatoid arthritis (RA) and Psoriasis (Fol...

Claims

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Application Information

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IPC IPC(8): C07K16/22A61P35/00A61K39/395C12N15/13C12N15/63A61K47/48A61P37/00
CPCC07K2317/565C07K2317/92C07K16/22C07K2317/24A61P19/00A61P19/02A61P27/00A61P27/02A61P29/00A61P35/00A61P35/04A61P37/00A61P37/02A61P43/00A61P5/14C12N15/11A61K39/395
Inventor 菲奥娜·阿尔丹赤松谦子罗伯特·B·迪布里吉大卫·B·鲍尔斯
Owner ABBVIE BIOTHERAPEUTICS
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