Neonatal Fc receptor (FcRn)-binding polypeptide variants, dimeric Fc binding proteins and methods related thereto

Abstract

The compositions and methods of the present invention are based, in part, on our discovery that an effector function mediated by an Fc-containing polypeptide can be altered by modifying one or more amino acid residues within the polypeptide (by, for example, electrostatic optimization). The polypeptides that can be generated according to the methods of the invention are highly variable, and they can include antibodies and fusion proteins that contain an Fc region or a biologically active portion thereof.

Description

RELATED APPLICATIONS [0001] This application is a continuation application of International Patent Application No. PCT / US2004 / 037929, filed Nov. 12, 2004, titled “NEONATAL Fc RECEPTOR (FcRn)-BINDING POLYPEPTIDE VARIANTS, DIMERIC Fc BINDING PROTEINS AND METHODS RELATED THERETO” which claims the benefit of U.S. Provisional Application Ser. No. 60 / 519,744, filed on Nov. 12, 2003, titled “ANTIBODIES AND VARIANTS THEREOF THAT CONTAIN ALTERED CONSTANT DOMAINS.” This application also claims the benefit of U.S. Application Ser. No. 60 / 519,743, filed on Nov. 12, 2003, titled “FC RECEPTOR-BINDING POLYPEPTIDES, PH-SPECIFIC VARIANTS DERIVED BY ELECTROSTATIC OPTIMIZATION, AND USES THEREFOR.” This application also claims the benefit of U.S. Application Ser. No. 60 / 519,733, filed on Nov. 12, 2003, titled “MUTANTS DEFINED BY ELECTROSTATIC MODELING WITHIN THE HUMAN FC DOMAIN THAT CAN MODULATE HUMAN ANTIBODY HALF-LIFE.”[0002] This application is also related to PCT application PCT / US2004 / 037948, titl...

AI Technical Summary

Benefits of technology

[0013] The instant invention further provides techniques for identifying desirable amino acid mutations and methods for producing the polypeptides comprising such mutations. The methods include molecular modeling, which can be used to predict amino acid alterations in an amino acid sequence to alter (e.g., enhance or reduce) binding to an Fc receptor, e.g. a human neonatal Fc receptor. Generally, the methods begin with a “starting” or “target” polypeptide, or a complex (e.g. crystal structure or homology model) containing the first polypeptide bound to FcRn, and modification of the first polypeptide results in a “second” or “altered” polypeptide, which differs from the first polypeptide in a way that allows the altered polypeptide to perform better in a particular therapeutic or diagnostic application. For example, the second polypeptide may more efficiently carry out one or more antigen-independent effector functions (e.g. altered half-life). The modeling can be carried out in silico.

[0253] In one embodiment, said Fc domain is mutated to reduce or eliminate binding to FcRn.

[0277] In one embodiment, the mutation increases the free energy of binding between altered Fc-containing polypeptide and FcRn when bound in a solvent, thereby decreasing binding affinity of the altered Fc-containing polypeptide for FcRn.

[0278] In one embodiment, the mutation decreases the free energy of binding between altered Fc-containing polypeptide and FcRn when bound in a solvent, thereby increasing binding affinity of the altered Fc-containing polypeptide for FcRn.

Problems solved by technology

This is not to say that present antibody-based therapies have been entirely successful; in some instances, the limited circulation time and / or low bioavailability of a therapeutic results in a relatively low percentage of patients that exhibit a complete response to an antibody-based therapeutics, or in other cases toxicity due to prolonged circulatory half-life or exposure of non-target tissue may preclude use of the antibody as a therapy.

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