Fc Fragment Mutations Enhancing FcRn and Fc Receptor Affinity
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Solution Overview
Problem
Current Fc fragments used in therapies for autoimmune and inflammatory diseases have limitations in terms of half-life and therapeutic efficacy, necessitating the development of variants with enhanced affinity for FcRn and Fc receptors to improve their blocking capabilities and immune system inhibition.
Innovation Solution
A variant of the parent polypeptide with specific mutations (334N, 352S, 378V, and additional mutations such as 434Y, 226G, P228L, P228R, 230S, 230T, 241L, 264E, 307P, 315D, 330V, 362R, 389T, and 389K) is developed, which exhibits increased affinity for FcRn and Fc receptors, thereby enhancing its therapeutic potential.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If standard Fc fragments are used in therapies, then the treatment can be administered, but the half-life and therapeutic efficacy are limited
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (334N, 352S, 378V, and combinations with other mutations like 434Y, 226G, P228L, etc.) in the Fc fragment sequence. These mutations alter the biochemical parameters of the Fc region to increase affinity for FcRn receptor and enhance therapeutic efficacy, directly resolving the contradiction between half-life and therapeutic effectiveness
Solution Approach 2:
The patent creates composite structures by combining multiple mutated Fc fragments with therapeutic proteins or antigens to form Fc fusion proteins. This composite approach allows the Fc portion to provide enhanced half-life and efficacy properties while the therapeutic portion maintains its specific biological function, thereby improving overall therapeutic performance
2Reliability
If Fc fragments are used to block Fc receptors, then immune system activation is inhibited, but the blocking capability and affinity are insufficient
Solution Approach 1:
The patent modifies the Fc fragment sequence through specific amino acid substitutions (334N, 352S, 378V, and combinations with mutations like 434Y, 226G, P228L, P228R, 230S, 230T, 241L, 264E, 307P, 315D, 330V, 362R, 389T, and 389K) to enhance binding affinity for Fc receptors. This increased affinity improves the blocking capability, allowing more effective inhibition of immune system activation by competing with pathogenic autoantibodies for Fc receptor binding
3Productivity
If Fc fragments are used to treat autoimmune diseases, then autoantibodies are targeted, but the elimination rate and toxicity reduction are limited
Solution Approach 1:
The patent introduces amino acid mutations (334N, 352S, 378V, and combinations with other mutations) that enhance FcRn binding affinity. This modification accelerates the elimination rate of pathogenic autoantibodies by facilitating their uptake and degradation through FcRn-mediated pathways, thereby increasing productivity in clearing harmful autoantibodies while reducing overall toxicity
Solution Approach 2:
The patent employs Fc fusion proteins that combine mutated Fc fragments with therapeutic proteins specifically targeted against autoantibodies. This composite structure enhances both the elimination rate through improved FcRn interaction and the specificity for targeting pathogenic autoantibodies, thereby reducing toxicity more effectively than standard Fc fragments
Data Source
AI summary
Disclosed is a variant of a parent polypeptide including an Fc fragment, the variant having an increased affinity for the FcRn receptor, and an increased affinity for at least one receptor of the Fc fragment (FcR) chosen from the FcγRI (CD64), FcγRIIIa (CD16a) and FcγRIIa (CD32a) receptors, relative to that of the parent polypeptide, characterised in that it includes: (i) the four mutations 334N, 352S, 378V and 397M; and (ii) at least one mutation chosen from 434Y, 434S, 226G, P228L, P228R, 230S, 230T, 230L, 241L, 264E, 307P, 315D, 330V, 362R, 389T and 389K; the numbering being that of the EU index or the Kabat equivalent.