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Anti-Fc-gamma RIIB receptor antibody and uses therefor

An antibody and receptor technology, applied in the direction of antibodies, anti-receptors/cell surface antigens/cell surface determinants, immunoglobulins, anti-inflammatory agents, etc., can solve problems such as functional differences

Inactive Publication Date: 2007-10-10
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] FcγRIIA and FcγRIIB isoforms contain very similar extracellular domains (approximately 92% amino acid sequence identity), but differ in their cytoplasmic Functional difference of FcγRIIB

Method used

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  • Anti-Fc-gamma RIIB receptor antibody and uses therefor
  • Anti-Fc-gamma RIIB receptor antibody and uses therefor
  • Anti-Fc-gamma RIIB receptor antibody and uses therefor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 10

[0288] Example 1.0 Materials and methods

[0289] 1.1 Materials

[0290] Reverse transcription PCR using Perkin Elmer Life Sciences GeneAmp TM conduct.

[0291] pGEX-4T2 plasmid, protein A column and reagents, and protein G FcyRIII: columns and reagents were obtained from Amersham Pharmacia Biotech. Ni-NTA columns and reagents were from Qiagen, Valencia, CA. Centriprep-30 concentrators were from Millipore, Bedford, MA. SDS-polyacrylamide gels and polyvinylidene fluoride membranes were obtained from NOVEX, San Diego, CA. FuGENE(R) 6 was obtained from Roche.

[0292] Encodes human FcγRIIA (CD32A; His 131 allotype), FcγRIIB (CD32B), and FcγRIIIA (CD16A; Val 158 allotype) and the glucose-6-phosphate isomerase (GPI) isoform of FcyRIIB and the cDNAs for the extracellular and transmembrane domains of FcyRIIA were provided by Dr. J. Ravetch (Rockefeller University, New York). FcγRIIA-Arg 131 Allotypes and FcγRIIIA-Phe 158 Allotypes were generated by site-directed mutagenesis...

Embodiment 2

[0317] Example 2.0 Properties of anti-FcγRIIB antibodies

[0318] 2.1 Materials

[0319] Anti-FcεRI MAb, 22E7 Mab binds FcεRI, with or without IgE bound to the receptor. 22E7 Mab was purified from the Hoffman-LaRoche cell line IGE4R: 22E7.2D2.1D11 (Risek, F., et al., 1991, J. Biol. Chem. 266: 11245-11251). Hoffman-LaRoche cells expressing 22E7 Mab were cultured in Iscove's modified Dulbecco's medium containing 10x FBS, 1x Pen-Strep, and 1x glutamine. 22E7 MAb was purified by protein A and protein G chromatography. 22E7 extracts were pooled and affinity for FcεRI was verified.

[0320] 2.2 RBL cell lines

[0321] The RBL48 cell line, derived from the parental rat mast cell line RBL-2H3 (ATCC #CRL-2256), expresses the alpha subunit of the high-affinity human IgE receptor (FcεRI) (Gilfillian A.M. et al., 1992, Immunology 149:2445- 2451). The cDNA clone (Muta T., et al.) of the human FcγRIIB1 full-length α subunit has been subcloned into a puromycin-selectable expression vec...

Embodiment 30

[0326] Example 3.0 Generation of bispecific antibodies

[0327] This example describes the construction and purification of bispecific antibodies that have a variant hinge region that lacks disulfide bond-forming cysteine ​​residues ("hingeless"). The construction of bispecific antibodies with wild-type hinge sequences is also described; these antibodies can be used to assess the efficiency of obtaining various types of antibody complexes.

[0328] 3.1 Construction of expression vector

[0329] All plasmids used to express full-length antibodies are based on a separate cistron system (Simmons et al., 2002, J. Immunol. Methods 263:133-147; Simmons et al., US Patent 5,840,523), which rely on a separate phoA Promoter (AP) (Kikuchi et al., 1981, Nucleic Acids Res.9: 5671-5678) to transcribe heavy and light chains, followed by trp Shine-Dalgamo sequence to initiate translation (Yanofsky et al., 1981, Nucleic Acids Res 9: 6647-6668; Chang et al., 1987, Gene 55: 189-196). In addit...

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PUM

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Abstract

The present application describes antibodies that selectively bind human FcyRIIB, with little or no binding to other human FcgammaRs, e.g., human FcgammaRIIA. The invention also provides isolated bispecific antibodies comprising an antibody that selectively binds FcgammaRIIB, and a second antibody that specifically binds an activating receptor. Various uses, including therapeutic uses, for those antibodies are also described, including administration with anti-tumor antibodies and methods of inhibiting immune responses and suppressing histamine release.

Description

[0001] This application is a nonprovisional application filed under 37 CFR §1.53(b)(1), claiming priority under 35 U.S.C.§119(e) to U.S. Provisional Application Serial No. 60 / 606,851, filed September 2, 2005, at Its entire contents are hereby incorporated by reference. field of invention [0002] The present invention pertains to antibodies that preferentially bind human FcyRIIB over human FcyRIIA, and uses of those antibodies. Background of the invention [0003] Antibodies bind to an antigen and neutralize the antigen by preventing its binding to its endogenous target (eg, a receptor or ligand) or by inducing an effector response that results in the removal of the antigen. To effectively remove and / or destroy foreign antigens, antibodies should exhibit both high affinity for their antigen and efficient effector functions. Antibodies with multiple specificities (such as, for example, bispecific antibodies) are useful ...

Claims

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Application Information

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IPC IPC(8): C07K16/00A61P37/08C07K16/28A61P37/06A61K39/395
CPCC07K7/06C07K5/0812C07K7/08C07K16/283C07K16/468C07K2316/96C07K2317/24C07K2317/56C07K2317/565C12N2799/026C07K2317/76A61P11/06A61P17/00A61P19/02A61P25/00A61P29/00A61P37/02A61P37/04A61P37/06A61P37/08A61P43/00A61P5/14A61P9/10A61P3/10C07K16/28C07K16/00
Inventor 陈志远罗伯特·L·希尔兹吴家伦
Owner GENENTECH INC
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