Engineering high avidity CTLA4Ig for therapy of rheumatic diseases

Abstract

Rheumatoid arthritis (RA) is a progressive autoimmune disease affecting ~ 2% of adults in developed countries. Despite worldwide attempts to develop therapeutics for the disease, there is no cure. Bristol-Myers Squibb have been interested in exploring the possibility of blocking B7-1 (CD80) and B7-2 (CD86) by CTLA4Ig for the treatment of immunological diseases. The current patent disclosed their methods in engineering high avidity CTLA4Ig by systematic mutation of 20 amino acids in the extracellular domain of the CTLA4 molecules. One of the mutants showed ~ 2- to 4-fold increase in binding B7-1 and B7-2. More importantly, in a Phase II clinical trial involving 214 patients, the mutant protein appeared more potent than wild type CTLA4Ig.

• B7-1 and B7-2
• CD28
• CTLA4
• costimulatory molecules
• rheumatoid arthritis (RA)
• T
• cell activation