Title:
VARIANT INTEGRIN POLYPEPTIDES AND USES THEREOF
Document Type and Number:
WIPO Patent Application WO2004066914
Kind Code:
A3
Abstract:
Polypeptides comprising all or part of a variant integrin alpha subunit A domain and its flanking region are described. In solution or in membrane-associated form, the A domain polypeptides of the invention exists predominantly in a high affinity conformation. In the polypeptides of the invention, referred to as variant integrin polypeptides, a crucial isoleucine or glutamic acid residue is altered. For example, the glutamic acid can be either deleted or replaced with different amino acids residue, e.g., glutamine, aspartic acid, or alanine. The variant integrin polypeptides of the invention selectively impair binding or activation-dependent ligands, but not independent ligands. They are useful in screening assays for the identification of molecules that enhance binding of variant polypeptides with impaired binding. In addition, they are useful in distinguishing between activation-dependent ligands and activation-independent ligands. They are also useful for generating antibodies, e.g., monoclonal antibodies, which bind to the impaired form of an integrin. Some such antibodies recognize an epitope that is either not present or not accessible on an integrin that is in the high affinity conformation. The variant integrin polypeptides of the invention can be derived from any integrin alpha subunit that could be used therapeutically.
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Inventors:
ARNAOUT M AMIN (US)
LI RUI (US)
XIONG JIAN-PING (US)
LI RUI (US)
XIONG JIAN-PING (US)
Application Number:
PCT/US2003/014919
Publication Date:
September 23, 2004
Filing Date:
May 12, 2003
Export Citation:
Assignee:
GEN HOSPITAL CORP (US)
ARNAOUT M AMIN (US)
LI RUI (US)
XIONG JIAN-PING (US)
ARNAOUT M AMIN (US)
LI RUI (US)
XIONG JIAN-PING (US)
International Classes:
C07K14/705; C07K16/28; C12N15/12; G01N33/53; G01N33/566; A61K38/00; A61K; C07K; (IPC1-7): C07K14/705; C12N15/12; G01N33/53
Foreign References:
| US20030078375A1 | 2003-04-24 |
Other References:
XIONG ET AL.: "An isoleucine-based allosteric switch controls affinity and shape shifting in integrin CD11b A-domain", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 275, no. 49, 8 December 2000 (2000-12-08), pages 38762 - 38767, XP002905767
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