Human CTLA-4 antibodies and their uses

An antibody and antigen technology, applied in the field of molecular immunology and the treatment of human diseases, which can solve problems such as incomplete understanding of the nature of molecules

Inactive Publication Date: 2012-10-10
ER SQUIBB & SONS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it is clear in some cases that soluble molecules such as interleukin (IL)-1 (Weaver and Unanue, supra) and membrane receptors involved in intercellular adhesions (Springer, Nature 346:425 (1990)) can provide co-stimulatory signals, this The molecular nature of the second signal is not fully understood

Method used

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  • Human CTLA-4 antibodies and their uses
  • Human CTLA-4 antibodies and their uses
  • Human CTLA-4 antibodies and their uses

Examples

Experimental program
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preparation example Construction

[0184] The production of bispecific and multispecific molecules of the invention can use chemical techniques (see e.g. Kranz (1981) Proc. Natl. Acad. Sci. USA 78:5807), "polydoma" technology (see e.g. DNA technology. The bispecific and multispecific molecules of the invention can also be prepared by linking the binding specificity moieties of the components, such as anti-FcR and anti-human CTLA-4 binding specificity moieties, using methods known in the art and as described herein. method described. For example, the binding specificities of each bispecific and multispecific molecule can be generated individually and then linked to each other. When the specific moieties to be bound are proteins or peptides, various coupling or cross-linking agents can be used for covalent attachment. Examples of crosslinkers include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), N-succinimidyl-3-(2-pyridine dithio)propionate (SPDP), and sulfosuccinimidyl-4-(N-maleimidome...

Embodiment 1

[0273] Example 1 Generation of Cmu-targeted mice

[0274] Construction of CMD targeting vector

[0275] Plasmid pICEmu contains the EcoRI / XhoI fragment of the murine Ig heavy chain locus spanning the mu gene obtained from the Balb / C genomic lambda phage library (Marcu et al., Cell 22:187, 1980). This genomic fragment was subcloned into the XhoI / EcoRI site in plasmid pICEMI9H (Marsh et al., Gene 32:481-485, 1984). The heavy chain sequence included in the plasmid pICEmu extends from an EcoRI site just downstream of the 3' end of the mu intronic enhancer to an XhoI site approximately 1 kb downstream of the last transmembrane exon of the mu gene; but passage in E.coli Many mu-transition repeat regions have been deleted during the process.

[0276] Targeting vectors were constructed as follows (see figure 1): A 1.3 kb HindIII / SmaI fragment was excised from plasmid pICEmu and subcloned into HindIII / SmaI digested plasmid pBluescript (Stratagene, LaJolla, CA). This plasmid pICEmu ...

Embodiment 2

[0286] Example 2. Generation of HCo12 transgenic mice

[0287] HCo12 human heavy chain transgene

[0288] The HCo12 transgene was generated by co-injection of the 80 kb insert of pHC2 (Taylor et al., 1994, Int. Immunol., 6:579-591) and the 25 kb insert of pVx6. Plasmid pVx6 was constructed as described below.

[0289] An 8.5 kb HindIII / SalI DNA fragment, including the germline human VH1-18 (DP-14) gene together with approximately 2.5 kb of 5' flanking genomic sequence and 5 kb of 3' flanking genomic sequence, was subcloned into plasmid vector pSP72 (Promega, Madison , WI) to generate plasmid p343.7.16. The 7 kb BamHI / HindIII DNA fragment, including the germline human VH5-51 (DP-73) gene together with approximately 5 kb of 5' flanking genomic sequence and 1 kb of 3' flanking genomic sequence, was cloned into Plasmid p251f was generated based on the pBR322 base plasmid cloning vector pGPIf (Taylor et al., 1992, Nucleic Acids Res. 20: 6287-6295). New cloning vector derived fro...

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Abstract

The present invention provides novel human sequence antibodies against human CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.

Description

[0001] Related Application Citations [0002] This application claims the benefit of US Provisional Patent Application Serial No. 60 / 150.452, the contents of which are hereby incorporated by reference in their entirety. field of invention [0003] The present invention relates generally to molecular immunology and treatment of human disease. In particular, the present invention relates to novel anti-human CTLA-4 human sequence antibodies and methods for using these antibodies to treat human diseases and infections. Background of the invention [0004] The vertebrate immune system requires multiple signals for optimal immune activation, see, e.g., Janeway, Cold Spring Harbor Symp. Quant. Biol. 54:1-14 (1989); Paul William E, ed., Raven Press, N.Y., Fundamental Immunology, 4 th edition (1998), especially Chapters 12 and 13, pp. 411-478. The interaction between T lymphocytes (T cells) and antigen presenting cells (APCs) is essential for the immune response. The levels of ma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N15/13C07K16/28A61K39/395A01K67/027C12N5/10C12N5/20A61K39/00A61K38/19A61P35/00A61K38/00A61P25/28A61P31/04A61P31/10A61P31/12A61P37/02C07K16/18C07K19/00C12N15/02C12N15/09C12N15/85
CPCA01K2267/0325C07K2319/00C07K16/2818A01K2267/01A01K2227/105C07K2317/21A01K2217/05C07K2317/732C12N15/8509A01K2217/00A01K2217/075A01K67/0278A01K67/0276A61K2039/505A01K2207/15A61P13/08A61P25/28A61P31/00A61P31/04A61P31/10A61P31/12A61P31/18A61P33/00A61P35/00A61P37/02A61P37/04A61P37/06Y02A50/30C07K16/18
Inventor 艾伦·J·科曼爱德华·L·霍克尼尔斯·朗伯格亚什万特·M·德奥蒂博尔·P·凯莱尔
Owner ER SQUIBB & SONS INC
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