Antibodies with Enhanced or Suppressed Effector Function

Abstract

Rationally designed antibodies and polypeptides that comprise two Fc region amino acid substitutions that synergistically provide enhanced selectivity and binding affinity to a target Fc receptor are provided. The polypeptides comprise Fc region mutations at two positions that synergistically make the polypeptides more effective when incorporated in antibody therapeutics than those having wild-type Fc components.

Description

CROSS-REFERENCE[0001]This application claims priority to U.S. Provisional Application No. 61 / 436,584, filed Jan. 26, 2011, and U.S. Provisional Application No. 61 / 318,583, filed Mar. 29, 2010. The contents of both provisional applications are incorporated in their entirety by reference herein.FIELD OF INVENTION[0002]The present invention relates to antibodies, fusion proteins and polypeptides. Specifically, the instant invention relates to rationally designed antibodies and polypeptides that comprise Fc region amino acid substitutions that synergistically provide enhanced selectivity and binding affinity to a target Fc receptor.BACKGROUND OF THE INVENTION[0003]Antibodies are proteins which exhibit binding specificity to a specific antigen. Native antibodies are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while...

AI Technical Summary

Benefits of technology

[0024]Another embodiment provides a polypeptide wherein the amino acid modifications produce amino acid interactions and dynamics that result in enhanced binding free energy to a first Fcγ receptor while diminishing binding affinity to a second Fcγ receptor compared to a polypeptide that lacks the at least three or more amino acid modifications. The first Fcγ receptor may be FcγRIIIa receptor and the second Fcγ receptor may be FcγRIIa or FcγRIIb.

[0061]In an aspect described herein are polypeptides, said polypeptides comprising a variant Fc region with two amino acid substitutions, wherein the polypeptide is more effective at mediating inhibition of inflammatory immune responses relative to wild type. In certain embodiments, the polypeptide comprising a variant Fc region is about 2 fold more effective in mediating inhibition of inflammatory immune responses relative to wild type. In some embodiments, the polypeptide comprising a variant Fc region is about 10 fold more effective in mediating inhibition of inflammatory immune responses relative to wild type. In certain embodiments, the polypeptide comprising a variant Fc region is about 50 fold more effective in mediating inhibition of inflammatory immune responses relative to wild type. In certain embodiments, the polypeptide comprising a variant Fc region is about 100 fold more effective in mediating inhibition of inflammatory immune responses relative to wild type.

Problems solved by technology

However, the variability is not evenly distributed through the variable domains of antibodies.

While binding of an antibody to the requisite antigen has a neutralizing effect that might prevent the binding of a foreign antigen to its endogenous target (e.g. receptor or ligand), binding alone may not remove the foreign antigen.

Although the effect of individual Fc region amino acid mutations on the binding with certain Fey receptors is well understood, previous studies fail to describe the effect of simultaneous changes to multiple amino acids.

Additionally, the prior art does not suggest suitable replacements for substituted Fc region amino acids to obtain optimal binding to the FcγR of interest, including modification of effector function of a wild type molecule that already has detectable effector function.

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