Fc Antibody Fc Region Mutations for Selective Receptor Binding
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Solution Overview
Problem
Current antibody pharmaceuticals, such as IgG1, have enhanced binding to activating FcγRIIa, leading to increased risk of thromboembolism and antigenicity, while variants with improved FcγRIIb binding often maintain or decrease binding to FcγRIIa allotypes, limiting their therapeutic efficacy and safety for autoimmune diseases.
Innovation Solution
Development of polypeptides with the IgG Fc region that have maintained or decreased binding activities towards FcγRIIa allotypes and enhanced FcγRIIb-binding activity through specific amino acid substitutions, specifically substituting Pro at position 238 with Asp and other targeted alterations, to achieve improved selectivity and immunosuppressive action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amino acid substitutions are introduced to enhance FcγRIIb-binding activity, then immunosuppressive efficacy is improved, but binding activity towards FcγRIIa allotypes may increase leading to thromboembolism risk
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions at particular positions (238, 328, 331) in the Fc region to selectively enhance FcγRIIb binding while maintaining or decreasing FcγRIIa binding. This localized modification approach allows differential interaction with different FcγR allotypes, achieving high FcγRIIb selectivity without proportionally increasing FcγRIIa binding, thereby improving immunosuppressive efficacy while limiting thromboembolism risk.
2Reliability
If Fc region variants with higher FcγRIIb binding are developed, then therapeutic efficacy for autoimmune diseases is improved, but binding selectivity may be compromised
Solution Approach 1:
The patent applies parameter changes by systematically varying amino acid substitutions at positions 238, 328, and 331 in the Fc region to optimize the balance between FcγRIIb binding affinity and FcγRIIa binding affinity. By changing these specific parameters (amino acid types at specific positions), the patent achieves variants with enhanced FcγRIIb binding while maintaining appropriate FcγRIIa binding levels, thus improving therapeutic efficacy while preserving binding selectivity.
Data Source
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AI summary
An objective of the present invention is to provide a polypeptide containing an Fc region having maintained or decreased binding activities towards both allotypes of FcγRIIa, types H and R, and having enhanced FcγRIIb-binding activity in comparison with a parent polypeptide; a pharmaceutical composition containing the polypeptide; an agent for treating or preventing immunological inflammatory diseases that includes the pharmaceutical composition; a production method thereof; and a method for maintaining or decreasing binding activities towards both allotypes of FcγRIIa and enhancing the FcγRIIb-binding activity. Specifically, it is found that a polypeptide containing an antibody Fc region that has an alteration of substituting Pro at position 238 (EU numbering) with Asp or Leu at position 328 (EU numbering) with Glu enhances FcγRIIb-binding activity, and maintains or decreases binding activities towards both allotypes of FcγRIIa, types H and R. It is also found that a polypeptide containing an antibody Fc region that contains an alteration of substituting Pro at position 238 (EU numbering) with Asp and several other alterations, enhances FcγRIIb-binding activity, and maintains or decreases binding activities towards both allotypes of FcγRIIa, types H and R.