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Anti-VEGF antibodies

An antibody, a technology for synthesizing antibodies, applied in the direction of antibodies, anti-inflammatory agents, anti-bacterial drugs, etc., can solve the problems of application, lack of systematic and quantitative methods, etc.

Active Publication Date: 2006-11-15
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these efforts are sometimes successful and not applied in a systematic and quantitative manner

Method used

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  • Anti-VEGF antibodies
  • Anti-VEGF antibodies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-G6 and B20

[0316] Example 1 - G6 and B20 derived antibodies

[0317] (a) Selection of high-affinity anti-VEGF Fab clones

[0318] Selection methods for high affinity anti-VEGF Fab clones involved various combinations of solid-supported and solution-bound sorting. Antibody phage libraries were panned with target antigen coated on NUNC 96-well Maxisorp immunoplates at a concentration of 5 ug / ml in solid-supported sorting. In the solution-binding sorting method, the phage library was incubated with biotinylated antigens at decreasing concentrations in solution, and then the antigens were coated on 96-well Maxisorp plates (2-5 ug / ml). Neutravidin capture. Decreasing concentrations allow for higher stringency in panning for tighter binders. For the target antigen mVEGF, a two-step sorting strategy was developed as follows, in step 1, strong binders were separated from the naive library by solid-phase-supported selection, and then in step 2, those with higher affinity Binders can be separa...

Embodiment 2-

[0350] Example 2 - Localization of VEGF Binding Sites on G6 and G6-23 Antibodies

[0351] Functional localization of G6 and G6-23 by shotgun alanine and analogue scanning

[0352] Functional mapping of G6 and G6-23 by shotgun alanine and homolog scanning was performed to identify residues important for binding hVEGF and to identify residues that could be further improved for binding VEGF Residues. We generated combinatorial phage libraries that allowed heavy or light chain CDR residues in separate libraries to be alanine or wild-type (alanine scanning), or homologous amino acids or wild-type (analog scanning).

[0353] Mutagenic oligonucleotides for shotgun scanning libraries

[0354] oligomer

sequence

H1-A

GCA GCT TCT GGC TTC ACC ATT KCC GMT KMT K

SG ATA CAC TGG GTG CGT CAG (SEQ ID NO: )

H2-A

AAG GGC CTG GAA TGG GTT GCA GST ATT RCT C

CT GST GST GGT KMT ACT KMT TAT GCC GAT AG

C GTC AAG GGC (SEQ ID NO: )

H3-A

...

Embodiment 3-G6 and G

[0380] Example 3-G6 and G6-23 derived antibodies

[0381] (a) Libraries for selection

[0382] Additional anti-VEGF antibodies were obtained by sorting phage from the shotgun alanine and homologue scanning libraries described in Example 2. Specifically, at specific residues, the residues being scanned were allowed to be changed to wild-type or alanine (alanine scanning), or wild-type or homolog residues (homolog scanning) ( Figure 14A and B). For G6, shotgun alanine and homolog scanning were performed on the G6 light and heavy chains, respectively, resulting in four libraries. For G623, shotgun alanine and homologue scans were performed on the G623 light chain and shotgun homolog scans were performed on the G623 heavy chain, resulting in three libraries. A G623 shotgun alanine scanning library was not prepared because, as discussed above, G623 is a high affinity antibody in which most of the residues critical for binding are located on the heavy chain. Mutating heavy chai...

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Abstract

Anti-VEGF antibodies and variants thereof, including those having high affinity for binding to VEGF, are disclosed. Also provided are methods of using phage display technology with naive libraries to generate and select the anti-VEGF antibodies with desired binding and other biological activities. Further contemplated are uses of the antibodies in research, diagnostic and therapeutic applications.

Description

[0001] related application [0002] This application claims U.S. Provisional Applications 60 / 491,877 filed August 1, 2003, 60 / 516,495 filed November 1, 2003, 60 / 570,912 filed May 12, 2004, May 13, 2004 Interest in 60 / 571,239, 60 / 576,315 filed June 1, 2004, and 60 / 580,757, filed June 18, 2004. technical field [0003] The present invention generally relates to selected anti-VEGF polypeptide sequences and antibodies having beneficial properties for research, therapeutic and diagnostic purposes. technical background [0004] Angiogenesis and VEGF [0005] Angiogenesis is an important cellular event in which vascular endothelial cells proliferate, prune and reorganize from a preexisting vascular network to form new blood vessels. There is strong evidence that the development of the vascular supply is essential for normal and pathological proliferative processes (Folkman and Klagsbrun (1987) Science 235:442-447). The delivery of oxygen and nutrients, as well as the excretion o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/00A61P35/00C07H21/04C07K14/705C07K16/22C07K16/32C12N15/13C12N15/62C12P21/04
CPCA61K2039/505C07K16/005C07K16/22C07K16/32C07K2317/31C07K2317/55C07K2317/56C07K2317/565C07K2317/92A61P1/04A61P1/18A61P11/00A61P13/02A61P15/08A61P17/02A61P17/06A61P19/02A61P27/02A61P27/06A61P29/00A61P31/04A61P35/00A61P35/02A61P37/02A61P43/00A61P5/14A61P9/10A61P3/10C07K2/00C07K16/00
Inventor 杰曼·富汉斯波得·格伯梁伟清弗雷德里克·A·费洛斯萨克德夫·S·西德休克里斯琴·韦斯曼
Owner GENENTECH INC
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