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Generation and selection of protein library in silico

A protein sequence and library technology, applied in proteomics, computer combinatorial chemistry, anti-growth factor immunoglobulin, etc., can solve unpredictable and labor-intensive problems

Inactive Publication Date: 2005-09-21
埃博马可西斯公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This repeated fine-tuning process can be labor-intensive and unpredictable

Method used

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  • Generation and selection of protein library in silico
  • Generation and selection of protein library in silico
  • Generation and selection of protein library in silico

Examples

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Embodiment

[0816] The methods of the present invention are used to construct antibody libraries in silico. Vascular endothelial growth factor (VEGF) was chosen as the antigen for the proof-of-principle experiments of the invention to demonstrate the invention in antibody design. For VEGF and its receptors (Muller YA, Christinger HW, Keyt BA, de Vos AM (1997) Structure 5, 1325-1338; Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, de Vos AM (1997) ) Cell 91, 695-704), the complex between VEGF and its humanized antibody (Muller YA, Christinger HW, Li B, Cunningham BC, Lowman HB, de Vos AM (1998) Structure 6, 1153-1167 , and the complex between VEGF and its mature antibody (Chen Y, Wiesmann C, Fuh G, Li B, Christinger HW, McKay P, de Vos AM (1999) J Mol Biol 293, 865-881), available Rich collection of sequence and structural information. These provide a good platform for testing the methods of the invention. By using the methods provided by the invention, by using the increased weal...

Embodiment 2

[0897] Example 2 Generation of Anti-VEGF Antibody Library for Framework Optimization

[0898] VEGF is a key angiogenic factor in development and is involved in the growth of solid tumors by stimulating endothelial cells. Murine monoclonal antibodies found to block VEGF-dependent cell proliferation and slow tumor growth in vivo (Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Nature 362, 841-844) . After grafting the antigen-binding loop, the murine antibody was humanized using random mutagenesis at some key framework positions (Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N( 1997) Cancer Res. 57, 4593-4599; Baca M, Presta LG, O'Connor SJ, Wells JA (1997) J Biol Chem 272, 10678-10684). Typically, after several rounds of site-directed mutagenesis and selection, humanized antibodies are generated by substituting non-human amino acids from the parental non-human antibody at certain pre-determined critical position...

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Abstract

The present invention provides methods for efficiently generating and screening protein libraries for optimal proteins with desired biological functions, such as improved binding affinity for biologically and / or therapeutically important target molecules. The method is performed in silico in a high-throughput fashion by mining the ever-expanding database of protein sequences in all living things, especially humans. In one embodiment, a method of constructing a designer protein library comprises the steps of: providing an amino acid sequence derived from a lead protein, referred to as a lead sequence; comparing the lead sequence with a plurality of test protein sequences; Select at least two peptide fragments having at least 15% sequence identity with the leader sequence from each test protein sequence, and the selected peptide fragments form a selection library; a library of designed proteins is formed by replacing the leader sequence with the selection library. Libraries of designed proteins can be expressed in vitro or in vivo to generate libraries of recombinant proteins that can be screened for new or improved functions relative to lead proteins, such as antibodies against a therapeutically important target.

Description

Background of the invention [0001] Cross References to Related Applications : [0002] This application is a continuation-in-part of U.S. Application Serial No. 10 / 153,159, filed May 20, 2002, entitled "Structure-Based Selection and Affinity Maturation of Antibody Libraries," also filed May 20, 2002, and entitled " Generation of affinity-matured antibody libraries in silico" is a continuation-in-part of Application No. 10 / 153,176, both of which were filed on April 17, 2002 in the U.S. Continuation-in-Part of Patent Application Serial No. 10 / 125,687, U.S. Patent Application Serial No. 10 / 125,687 claiming U.S. Provisional Application Serial No. 60 / 284,407, filed April 17, 2001, entitled "Construction of Human Antibody Libraries Based on Structures" Benefit. [0003] field of invention [0004] The present invention generally relates to the computer-aided design of proteins with binding affinities to target molecules, and more specifically, to the screening and identificati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/09G16B35/20C07K16/00C07K16/22C12N1/15C12N1/19C12N1/21C12N5/10G16B20/30G16B20/50G16B30/00G16B30/10
CPCC40B50/02C07K16/00C07K16/22C07K2317/24C07K2317/622C07K2319/00G06F19/18G06F19/22G16B35/00G16C20/60G16B20/00G16B30/00G16B20/30G16B30/10G16B35/20G16B20/50
Inventor 罗培志马克·赫斯荷钟苹羽王才郦曹亦成刘盛疆
Owner 埃博马可西斯公司
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