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Humanized antibodies and method for forming same

A humanized antibody, antibody technology, applied in chemical instruments and methods, biochemical equipment and methods, botanical equipment and methods, etc., can solve problems such as time-consuming, labor-intensive, and unsatisfactory

Inactive Publication Date: 2000-07-12
GENENTECH INC
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  • Claims
  • Application Information

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Problems solved by technology

However, this method involves repeated cycles of site-directed mutagenesis, isolation, and screening, which is time-consuming and labor-intensive, which is not ideal

Method used

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  • Humanized antibodies and method for forming same
  • Humanized antibodies and method for forming same
  • Humanized antibodies and method for forming same

Examples

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specific Embodiment I

[0067] Construction of phagemid vector and initial humanized anti-VEGF

[0068] The murine anti-VEGF monoclonal antibody A4.6.1 has already been described by Kim et al., Growth Factors 7, 53 (1992); Kim et al., Nature 362, 841 (1993). The first humanized Fab variant hu2.0 of A4.6.1 was constructed as follows: L κI-Cκ 1 light chain and human V H III-C H lγ 1 The deoxyuridine-containing template of the plasmid pAK2 for the Fd fragment of the heavy chain was subjected to site-directed mutagenesis (Carter et al., Proc. Natl. Acad. Sci. USA 89, 4285 (1992)). According to the sequence definitions in Kabat et al., Sequences of Proteins of Immunological Interest, (5th), Public Health Service, National Institutes of Health, Bethesda, MD (1991), the CDR sequences of A4.6.1 to be transplanted were selected, except CDR- In addition to H1, we extended CDR-H1 to include sequence and structural sequence, ie V H Residues 26-35 (Chothia et al., J. Mol. Biol. 196, 901 (1987)). The Fab co...

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Abstract

Described herein is a humanized antibody to vascular endothelial growth factor (VEGF). Also described herein is a method for rapidly producing and identifying framework mutations which improve the binding of humanized antibodies to their cognate antigens. In a preferred embodiment, non-human CDRs are grafted onto a human V1 kappa I-V HIII framework. Random mutagenesis of a small set of critical framework residues is also performed followed by monovalent display of the resultant library of antibody molecules on the surface of filamentous phage. The optimal framework sequences are then identified by affinity-based selection. Optionally, the selected antibodies can be further mutated so as to replace vernier residues which sit at the VL-VH interface by residues which match the non-human parent antibody. The methods described herein can be applied to any non-human antibody. Accordingly, humanized antibodies are provided.

Description

field of invention [0001] The present invention relates to humanized antibodies and methods of making humanized antibodies. In particular, the present invention relates to methods for preparing humanized antibodies using a monovalent phage display system, and antibody variants generated by random mutagenesis of a small set of key framework residues of a single human framework. More specifically, the invention relates to the humanization of murine antibodies that bind vascular endothelial growth factor (VEGF). Background of the invention [0002] Monoclonal antibodies (mAbs) have great potential as therapeutic agents, especially as they can be used to modulate the angiogenic system. For example, in some cases it may be necessary to modulate, for example, the angiogenic system when new capillaries form from the walls of existing small vessels. Angiogenesis is often important following injury or infection in order to stimulate a rapid growth of capillaries near damaged tissue...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/09A61K38/00A61K38/17A61K39/395A61P25/00A61P27/02A61P35/00C07K16/18C07K16/22C07K16/46C12N5/10C12N15/02C12N15/13C12N15/66C12P21/02C12P21/08
CPCC07K2317/565C07K2317/92C07K16/22A61K38/00C07K16/005C07K2317/55C07K2317/73C07K2317/56C07K2317/24C07K2317/569A61P25/00A61P27/00A61P27/02A61P35/00A61P43/00A61K39/00
Inventor J·A·韦尔斯M·巴卡L·G·普雷塔
Owner GENENTECH INC
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