Engineered IgG Fc Regions for Extended Serum Half-Life
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Solution Overview
Problem
There is a need for improved therapeutic IgGs that exhibit enhanced pH-dependent binding to FcRn to extend serum half-life and improve pharmacokinetic properties.
Innovation Solution
Engineered immunoglobulins with mutations Q311R, N434W, and M428E in the human wild-type IgG1 Fc region, altering binding to FcRn to extend serum half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If the Fc region of IgG is engineered to enhance FcRn binding, then serum half-life is extended, but the structural complexity of the antibody increases
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the Fc region (Q311R, N434W, M428E) to alter the chemical properties and binding characteristics of the antibody. These point mutations change local charge distribution and hydrophobicity, thereby enhancing FcRn binding affinity and extending serum half-life without requiring large structural modifications
Solution Approach 2:
The invention applies local quality by making targeted modifications only in the Fc region's neonatal Fc receptor binding site, specifically at positions 311, 428, and 434. This localized engineering approach allows enhancement of FcRn binding while preserving the overall antibody structure and other functional regions, minimizing structural complexity increase
2Reliability
If multiple amino acid mutations are introduced to alter FcRn binding, then binding affinity is improved, but manufacturing precision requirements increase
Solution Approach 1:
The patent applies partial action by introducing a specific combination of three mutations (Q311R, N434W, M428E) that collectively achieve the desired binding enhancement. Rather than attempting numerous mutations, this focused approach of three specific changes provides sufficient improvement in FcRn binding while keeping manufacturing complexity manageable through standardized mutagenesis protocols
Data Source
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AI summary
The present invention relates to compositions and methods for antibody-mediated therapy. In particular, provided herein are engineered immunoglobulins with altered half-life.