Self-Assembled Multabody Constructs With FcRn-Tuned Half-Life
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Solution Overview
Problem
Existing antibody-based therapeutics often require tuning to achieve desirable biodistribution and half-lives, and existing optimization techniques for IgG molecules can have unexpected effects on self-assembled polypeptide complexes.
Innovation Solution
Development of self-assembled polypeptide complexes with optimized Fc polypeptides and antigen-binding antibody fragments, featuring specific mutations to alter binding to FcRn and effector function, resulting in complexes with pharmacokinetic characteristics similar to reference IgG molecules and inducing antibody-dependent cellular phagocytosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing optimization techniques for IgG molecules are applied to self-assembled polypeptide complexes, then certain characteristics may be improved, but unexpected adverse effects occur on the complex's overall performance
Solution Approach 1:
The patent applies parameter changes by introducing specific mutations at defined positions within the Fc polypeptide sequence. These mutations (such as M252, I253, S254, T256, K288, M428, N434) systematically alter binding properties to FcRn and effector function, enabling precise control over pharmacokinetic characteristics while avoiding unexpected adverse effects through position-specific optimization
Solution Approach 2:
The invention implements local quality by making targeted mutations at specific positions within the Fc polypeptide rather than global modifications. This allows different regions of the Fc domain to have optimized properties - for example, mutations at positions 428 and 334 specifically enhance half-life through altered FcRn binding, while other positions can be optimized for effector function independently
2Duration of action of moving object
If Fc polypeptide mutations are introduced to alter binding to FcRn and effector function, then pharmacokinetic characteristics are improved, but complexity of the polypeptide structure increases
Solution Approach 1:
The patent employs parameter changes by introducing specific amino acid mutations at defined positions within the Fc polypeptide sequence. These mutations systematically alter binding properties to FcRn and effector function, enabling precise control over pharmacokinetic characteristics such as half-life while maintaining a relatively simple overall structure through position-specific optimization rather than global complexity
Data Source
AI summary
In aspects, a self-assembled polypeptide complex comprises (a) a plurality of first fusion polypeptides, each first fusion polypeptide comprising (1) an Fc polypeptide linked to (2) a nanocage monomer or subunit thereof, wherein the Fc polypeptide comprises a Fc chain having one or more mutations relative to a reference Fc chain of the same Ig class, and (b) a plurality of second fusion polypeptides, each second fusion polypeptide comprising (1) an antigen-binding antibody fragment linked to (2) a nanocage monomer or subunit thereof.