Fc Region Mutated Antibody for Regulatory T Cell Elimination
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Solution Overview
Problem
Current cancer treatments using antibody pharmaceuticals, such as anti-CTLA4 antibodies, face limitations in effectively eliminating regulatory T cells and exhausted T cells, which suppress immune responses, due to insufficient ADCC activity.
Innovation Solution
Development of antigen-binding molecules that combine a domain binding to immune response-suppressing molecules like CTLA4 with a T cell receptor complex-binding domain, enhancing ADCC activity by incorporating an FcRn-binding domain with reduced Fcγ receptor-binding activity, to target and eliminate regulatory and exhausted T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CTLA4 antibodies are used to treat cancer, then T cell activation is enhanced, but ADCC activity against regulatory T cells is insufficient
Solution Approach 1:
The patent modifies the Fc region of the antibody by substituting specific amino acids (such as L234F, L235E, P331S) to change the binding parameters of Fcγ receptors while maintaining or enhancing FcRn binding. This parameter change optimizes ADCC activity against regulatory T cells expressing CTLA4, thereby improving the reliability of antitumor effects while addressing the insufficient ADCC activity problem.
2Productivity
If Fc region amino acid substitutions are made to enhance ADCC activity, then binding to Fcγ receptor increases, but natural antibody function may be compromised
Solution Approach 1:
The patent carefully selects specific amino acid substitutions in the Fc region that enhance Fcγ receptor binding and ADCC activity while preserving essential antibody functions. The substitutions are designed to optimize rather than disrupt natural antibody function, maintaining stability while improving productivity.
Solution Approach 2:
The modifications are localized to specific regions of the Fc region (such as positions 234, 235, 331) rather than throughout the entire antibody structure. This local quality change allows enhancement of ADCC activity in specific functional domains while preserving the overall stability and natural functions of the antibody molecule.
3Object-affected harmful factors
If conventional antibody pharmaceuticals are used, then cytotoxic activity against cancer cells is achieved, but immune response suppression by regulatory T cells persists
Solution Approach 1:
The patent uses the Fc region of the antibody as an intermediary to engage Fcγ receptors on effector cells, thereby mediating ADCC activity against regulatory T cells. This intermediary mechanism allows the antibody to simultaneously maintain cytotoxic activity against cancer cells while eliminating immune-suppressing regulatory T cells through enhanced ADCC.
Data Source
AI summary
It was discovered that antigen-binding molecules comprising (i) a domain that binds to a molecule expressed on the surface of cells having immune response-suppressing functions, and (ii) a T cell receptor complex-binding domain exhibit more superior antitumor effects than conventional antigen-binding molecules by crosslinking T cells with cells having immune response-suppressing functions, and damaging the cells having immune response-suppressing functions.