DOMAINS OF THE CONSTANT REGION OF IMMUNOGLOBULINS WITH IMPROVED STABILITY

摘要

The invention provides an isolated polypeptide including an immunoglobulin CSUBH/SUB3 region domain polypeptide, or functional fragment thereof, having at least one Pro to GIy substitution and exhibiting enhanced stability, including an enhanced folding rate, compared to an unsubstituted CSUBH/SUB3 domain, wherein the at least one Pro to GIy substitution comprises CSUBH/SUB3 residue Pro38 or a CSUBH/SUB3 domain equivalent thereof. Multimeric complexes of an immunoglobulin CSUBH/SUB3 region domain polypeptide, or functional fragment thereof, having at least one Pro to GIy substitution with a second immunoglobulin CSUBH/SUB3 region domain polypeptide also are provided by the invention. The multimeric complexes can include antibodies, antibody functional fragments such as Fd, Fv, Fab, F(ab'), F(ab)SUB2/SUB, F(ab')SUB2/SUB, single chain Fv (scFv), chimeric antibodies, diabodies, triabodies, tetrabodies or minibody and other binding polypeptides having an immunoglobulin CSUBH/SUB3 region domain polypeptide such as a peptibody or an Fc fusion polypeptide. An isolated population of polypeptides including a plurality of immunoglobulin CSUBH/SUB3 region domain polypeptides, or functional fragments thereof, is further provided. Each CSUBH/SUB3 region domain polypeptide within the populations includes at least one Pro to GIy substitution and exhibits enhanced stability, including an enhanced folding rate, compared to an unsubstituted CSUBH/SUB3 domain, wherein the at least one Pro to GIy substitution comprises CSUBH/SUB3 residue Pro38 or a CSUBH/SUB3 domain equivalent thereof. The invention further provides a method of producing a multimeric binding polypeptide and a method of treating a pathological condition characterized by aberrant cell growth.