Modified Antibody Variable Regions to Prevent T-Cell Cross-Linking
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Solution Overview
Problem
Conventional bispecific antibodies that bind to multiple antigens simultaneously can induce adverse reactions due to cross-linking with FcγR, limiting their systemic administration and efficacy in treating conditions like cancer.
Innovation Solution
Development of an antigen-binding molecule with altered antibody variable regions that allow binding to two different antigens independently and a third antigen, while reducing FcγR binding activity, thereby minimizing cross-linking and adverse reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional bisspecific antibodies bind to multiple antigens simultaneously, then they can target multiple cancer-related antigens, but they induce adverse reactions due to cross-linking with FcγR
Solution Approach 1:
The antibody molecule is divided into separate functional modules: variable regions for antigen binding and Fc regions for effector function. The bispecific antibody comprises a first antibody molecule binding to a first antigen and a second antibody molecule binding to a second antigen, with at least one having reduced FcγR binding activity, thereby segmenting the cross-linking function from the antigen-binding function
Solution Approach 2:
Different parts of the antibody system are given different properties: the variable regions are engineered for high affinity binding to specific antigens (first and second antigens), while the Fc regions are modified to have reduced binding activity to FcγR, creating local functional differentiation that prevents harmful cross-linking while maintaining antigen-targeting capability
Solution Approach 3:
The binding affinity parameter of the Fc region to FcγR is deliberately reduced through amino acid substitutions (e.g., L234A, L235A, L234F, L235F, L234V, L235V, L234E, L235E, L234D, L235D, L234Q, L235Q, L234H, L235H, L234P, L235P, L234S, L235S, L234T, L235T, L234N, L235N, L234K, L235K, L234R, L235R, L234M, L235M, L234C, L235C, L234G, L235G, L234A, L235A, L234D, L235D, L234E, L235E, L234Q, L235Q, L234H, L235H, L234P, L235P, L234S, L235S, L234T, L235T, L234N, L235N, L234K, L235K, L234R, L235R, L234M, L235M, L234C, L235C, L234G, L235G, L234A, L235A, L234D, L235D, L234E, L235E, L234Q, L235Q, L234H, L235H, L234P, L235P, L234S, L235S, L234T, L235T, L234N, L235N, L234K, L235K, L234R, L235R, L234M, L235M, L234C, L235C, L234G, L235G) in the Fc region, changing the physical-chemical parameter of FcγR binding activity to reduce harmful cross-linking
2Reliability
If antibodies bind to FcγR to induce effector functions, then they can exert cytotoxic activity against cancer cells, but they cause cross-linking of effector cells leading to adverse reactions
Solution Approach 1:
The effector function is segmented from the antigen-binding function. The bispecific antibody uses modified Fc regions with reduced FcγR binding activity to minimize effector cell cross-linking, while maintaining the ability to bind antigens and recruit effector cells through alternative mechanisms or controlled interactions
Solution Approach 2:
The binding affinity parameter between Fc region and FcγR is reduced through amino acid substitutions, changing the strength of interaction to prevent harmful cross-linking of effector cells while preserving sufficient activity for controlled cytotoxic response against cancer cells
Data Source
AI summary
The present inventors have successfully prepared an antigen-binding molecule comprising an antibody variable region that has binding activity against a molecule expressed on the surface of a T cell and a molecule expressed on the surface of any other immunocyte, but does not bind to these molecules at the same time. The present invention allows the preparation of an antigen-binding molecule capable of circumventing adverse reactions that may be caused by the cross-linking of T cells to other immunocytes, and provides an antigen-binding molecule suitable as a drug.