Anti-CD154 Antibodies With Abated FcR Binding
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Solution Overview
Problem
Current anti-CD154 antibodies used in immune therapies face challenges due to toxicity issues such as thrombogenic and clotting reactions, which reduce their efficacy and safety for treating inflammatory disorders, autoimmunity, and cancers.
Innovation Solution
Development of modified anti-CD154 antibodies with mutations in the Fc region that inhibit FcR binding and complement activation, maintaining therapeutic efficacy while preventing thrombotic events.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anti-CD154 antibodies are used to induce immune tolerance and suppress humoral immunity, then therapeutic efficacy is improved, but thrombogenic and clotting reactions occur causing toxicity
Solution Approach 1:
The patent divides the antibody structure into functional segments: the Fab region retains full binding affinity for CD154 to maintain therapeutic efficacy, while the Fc region is modified through amino acid substitutions (e.g., L234N, L235N, G236A) to specifically eliminate FcγR binding and complement activation. This segmentation allows independent optimization of efficacy and safety profiles.
Solution Approach 2:
The invention applies local quality changes by introducing specific mutations only in the Fc region's constant domains (CH2 and CH3) while leaving the variable regions and CDRs unchanged. The L234N, L235N, and G236A mutations locally alter the Fc region's interaction properties with FcγRs and complement proteins, creating a differentiated functional profile where the Fc region no longer mediates harmful effects while the Fab region maintains full therapeutic activity.
2Object-affected harmful factors
If Fc region mutations are introduced to prevent FcR binding and complement activation, then safety is improved by preventing thrombotic events, but potential loss of therapeutic function may occur
Solution Approach 1:
The patent converts the potentially harmful Fc-mediated effector functions into a benefit by eliminating them. The Fc region's ability to bind FcγRs and activate complement, which causes thrombogenicity and toxicity, is transformed into a safety feature through the L234N, L235N, and G236A mutations. This converts a harmful property into a beneficial safety characteristic while preserving the essential CD154 blocking function.
Solution Approach 2:
The invention applies parameter changes by systematically modifying the amino acid sequence parameters of the Fc region. The specific substitutions (L234N, L235N, G236A) change the chemical and physical parameters of the Fc region, altering its binding affinity for FcγRs and complement proteins. These parameter changes are precisely controlled to eliminate harmful interactions while maintaining the antibody's half-life and stability through preserved FcRn binding.
3Object-affected harmful factors
If Fc effector mechanisms are eliminated through mutation, then thrombogenicity is reduced, but ability to induce tolerance may be compromised
Solution Approach 1:
The patent introduces dynamics by creating a conditionally functional Fc region. The modified Fc region dynamically adapts its interactions: it maintains binding to FcRn for extended half-life and preserves structural integrity for proper Fab positioning, while dynamically rejecting binding to FcγRs and complement proteins. This dynamic selectivity allows the antibody to maintain tolerance-inducing capability through antigen-specific blockade while avoiding harmful Fc-mediated activation pathways.
Data Source
AI summary
Improved anti-CD154 antibodies are provided herein which have ablated FcR binding and/or complement binding/activation. The use of these antibodies for inducing tolerance and treating immune diseases including autoimmunity, inflammation and allergic disorders is disclosed herein.