Fcabs for CD137 Activation Without Liver Inflammation
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Solution Overview
Problem
Clinical development of CD137 agonist molecules has been hindered by dose-limiting high-grade liver inflammation and low clinical efficacy.
Innovation Solution
Development of antigen-binding Fc fragments (Fcabs) that preferentially bind to dimeric CD137 with higher affinity than monomeric CD137, and introduction of mutations to reduce Fcγ receptor binding, allowing for conditional activation of CD137 in the presence of a second antigen.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If agonistic anti-CD137 monoclonal antibodies are used to activate CD137, then T cell cytotoxicity and immune response are enhanced, but dose-limiting high-grade liver inflammation occurs
Solution Approach 1:
The antibody molecule is engineered with non-uniform binding properties: the Fab regions bind CD137 with high affinity to activate immune cells, while the Fc region has reduced binding to Fcγ receptors to minimize liver inflammation. This local differentiation of binding properties allows selective activation of desired immune pathways while avoiding harmful pathways.
Solution Approach 2:
The patent modifies the Fc region of the antibody to change its binding parameters to Fcγ receptors, specifically reducing affinity through mutations. This parameter change allows the antibody to maintain CD137 agonist activity while reducing unwanted interactions with Fcγ receptors that lead to liver inflammation.
2Reliability
If full-length IgG antibodies are used to bind CD137, then CD137 activation is achieved, but Fcγ receptor binding causes unwanted immune activation and toxicity
Solution Approach 1:
The harmful Fc region is extracted or removed from the antibody molecule, replacing it with an Fc fragment that lacks Fcγ receptor binding capability. This extraction of the problematic component allows retention of CD137 binding and activation functions while eliminating the source of unwanted immune activation and toxicity.
Solution Approach 2:
The patent uses a modified Fc fragment instead of a full-length IgG antibody. This shortened molecule performs the essential CD137 binding and activation function without the additional complexity and harmful effects of the complete Fc region, effectively using a simplified version that achieves the goal without the drawbacks.
3Reliability
If high doses of anti-CD137 antibodies are administered to overcome low clinical efficacy, then immune activation is enhanced, but liver inflammation and toxicity increase
Solution Approach 1:
The patent changes the binding parameters of the antibody to Fcγ receptors by reducing affinity through Fc region mutations. This allows the antibody to maintain or enhance CD137 activation efficacy at lower doses without triggering the Fcγ receptor-mediated pathways that lead to liver toxicity, effectively decoupling efficacy from toxicity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The Fcabs achieve high activity in activating CD137 without inducing liver inflammation, and demonstrate enhanced tumour growth suppression when used as bispecific molecules binding to both CD137 and a tumour antigen.
Implementation Method 1
Fc fragments (Fcabs) that preferentially bind to dimeric CD137 with higher affinity than monomeric CD137
Implementation Method 2
introduction of mutations to reduce Fcγ receptor binding
Data Source
AI summary
The invention relates to specific binding members that bind CD137. The specific binding members comprise a CD137 antigen-binding site located in a constant domain of the specific binding member and find application in the treatment of cancer and infectious diseases, for example.