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Soluble CTL A4 mutant molecules and use thereof

A mutant and soluble technology, applied in the field of soluble CTLA4 molecules, can solve problems such as affinity impact

Inactive Publication Date: 2003-09-10
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, it was determined that the MYPPPY motif of CTLA4 and CD28 is important for binding to CD80, but certain non-conserved amino acid residues in the CDR1-like region and CDR3-like region of CTLA4 also contribute to the enhancement of the binding affinity of CTLA4 to CD80
[0013] Shows that CTLA4Ig effectively blocks CD80-associated T cell co-stimulation, but not as effectively as when blocking CD86-associated responses

Method used

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  • Soluble CTL A4 mutant molecules and use thereof
  • Soluble CTL A4 mutant molecules and use thereof
  • Soluble CTL A4 mutant molecules and use thereof

Examples

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Embodiment 1

[0112] This example provides an illustration of the method used to generate a nucleotide sequence encoding a soluble CTLA4 mutant molecule of the invention. Single point mutant L104EIg was generated and tested for binding kinetics to CD80 and / or CD86. The L104EIg nucleotide sequence was used as a template to generate the double-site mutant CTLA4 sequence-L104EA29YIg, and the binding kinetics of L104EA29YIg to CD80 and / or CD86 was tested. CTLA4Ig codon-based mutagenesis :

[0113] A mutagenesis and screening strategy was developed to identify mutant CTLA4Ig molecules with slower dissociation rates ("off" rates) from CD80 and / or CD86 molecules. Single point mutant nucleotide sequences were generated using CTLA4Ig (US Patent Nos. 5,844,095, 5,851,795, and 5,885,796; ATCC Deposit No. 68629) as a template. Designed for random mutagenesis of specific cDNA codons by allowing any base in codon positions 1 and 2, but only guanine and thymine in position 3 (XXG / T; also known as NNG / T...

Embodiment 2

[0116] A description of the screening methods used to identify the single-site and double-site mutant CTLA4 polypeptides expressed from the constructs described in Example 1, wherein the mutant CTLA4 polypeptides exhibit binding affinity for the CD80 and CD86 antigens, is provided below Higher than non-mutated CTLA4Ig molecules.

[0117] Current in vitro and in vivo studies demonstrate that CTLA4Ig by itself cannot completely block the priming of antigen-specific activated T cells. In vitro studies measuring inhibition of T cell proliferation using CTLA4Ig and CD80 or CD86 specific monoclonal antibodies showed that anti-CD80 monoclonal antibodies did not enhance CTLA4Ig inhibition. Anti-CD86 monoclonal antibodies, however, enhanced the inhibition, suggesting that CTLA4Ig was not as effective in blocking CD86 interactions. These data support the earlier findings of Linsley et al. ( Immunity , (1994), 1:793-801), the finding that inhibition of CD80-mediated cellular responses...

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Abstract

The present invention provides soluble CTLA4 mutant molecules that bind CD80 and / or CD86 antigens with higher affinity than wild-type CTLA4 or non-mutated CTLA4Ig. The soluble CTLA4 molecule has a first amino acid sequence comprising the extracellular domain of CTLA4, wherein certain amino acid residues in the S25-R33 region and the M97-G107 region are mutated. A mutant molecule of the invention may also comprise a second amino acid sequence that enhances the solubility of said mutant molecule.

Description

[0001] Various publications are cited throughout this application. The disclosures of these publications in their entirety are incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. field of invention [0002] The present invention relates to the field of soluble CTLA4 molecules mutated from wild-type CTLA4 to retain the ability to bind CD80 and / or CD86. Background of the invention [0003] Antigen-nonspecific intercellular interactions between T lymphocytes and antigen-presenting cells (APCs) generate T-cell co-stimulatory signals that elicit T-cell responses against antigens (Jenkins and Johnson (1993) Curr. Opin. Immunol, 5:361-367). Costimulatory signals determine the magnitude of the T cell response to antigen and whether this response is activated or inactivated in subsequent responses to antigen (Mueller et al. (1989) Annu. Rev. Immunol. 7:445-480). [0004] T cell activation in the ab...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/09A61K38/00A61K45/00A61P37/00A61P37/06C07KC07K14/47C07K14/705C07K16/00C07K19/00C12N5/10C12P21/02C12Q1/02G01N33/68
CPCG01N33/502G01N33/5005A61K38/00G01N33/5008C07K14/70521G01N33/68G01N33/505C07K2319/30A61P37/00A61P37/02A61P37/06C07K14/705
Inventor R·J·皮奇J·R·奈穆拉P·S·林斯利J·巴约拉斯
Owner BRISTOL MYERS SQUIBB CO
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