Fc Mutants Modulating Receptor Binding Ratios
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Solution Overview
Problem
Current therapies for autoimmune diseases, such as lupus and rheumatoid arthritis, face challenges in effectively regulating B cell activation and antibody production due to aberrant expression or functionality of Fcγ receptors, leading to hyperactivation and inappropriate production of autoantibodies.
Innovation Solution
Development of antibody Fc variants with preferential binding to the inhibitory FcγRIIB receptor to inhibit autoreactive lymphocyte and effector cell activation, achieved by determining the activating to inhibitory receptor binding affinity ratio (A/I ratio) and modifying the Fc region to enhance binding to FcγRIIB while reducing binding to activating receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody therapies are used to treat autoimmune diseases, then B cell activation and antibody production are targeted, but aberrant Fcγ receptor expression or functionality leads to hyperactivation and inappropriate autoantibody production
Solution Approach 1:
The patent modifies the Fc region of antibodies to create variants with altered binding properties. Specifically, the Fc variants are engineered to have preferential binding to the inhibitory FcγRIIB receptor compared to activating Fcγ receptors. This local modification of the Fc region creates differential binding affinity that selectively targets inhibitory pathways while maintaining or reducing activation signals, thereby resolving the contradiction between effective B cell regulation and prevention of hyperactivation
Solution Approach 2:
The patent employs amino acid substitutions in the Fc region (such as at positions 232, 235, 238, 241, 244, 256, 260, 264, 267, 270, 273, 276, 280, 283, 286, 289, 292, 295, 298, 301, 304, 307, 310, 313, 316, 319, 322, 325, 328, 331, 334, 337, 340, 343, 346, 349, 352, 355, 358, 361, 364, 367, 370, 373, 376, 379, 382, 385, 388, 391, 394, 397, 400) to change the binding parameters of the antibody. These parameter changes in the Fc region alter the affinity and specificity for different Fcγ receptor subclasses, enabling preferential engagement of inhibitory receptors and thereby controlling the balance between activation and inhibition signals
2Reliability
If Fc region modifications are made to enhance binding to FcγRIIB, then inhibitory signaling is improved, but binding to activating receptors may be reduced
Solution Approach 1:
The patent inverts the conventional approach by designing Fc variants that prioritize binding to inhibitory FcγRIIB receptor over activating Fcγ receptors. Instead of enhancing activation signals, the Fc variants are engineered with amino acid modifications that create preferential affinity for the inhibitory receptor. This inversion of the binding hierarchy allows the antibody to deliver inhibitory signals preferentially, counterbalancing the hyperactivation seen in autoimmune diseases while maintaining therapeutic efficacy
Data Source
AI summary
The present invention provides reagents, methods and systems for predicting the inhibitory activity of an antibody or variant thereof comprising: determining a binding affinity of the antibody or variant thereof to a Fc activating receptor; determining a binding affinity of the antibody or variant thereof to a Fc inhibitory receptor, and calculating the ratio of said activating binding affinity to said inhibitory binding affinity (A/I ratio), wherein the magnitude of said ratio is less than one (1).