Antigen-binding molecule containing modified antibody variable region
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Solution Overview
Problem
Conventional bispecific antibodies that bind to multiple antigens simultaneously can cause adverse reactions due to cross-linking with FcγR, limiting their systemic administration and efficacy in treating 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 avoiding cross-linking and adverse reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional bispecific antibodies bind to multiple antigens simultaneously, then they can target multiple cancer-related antigens, but they cause 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 variable region is segmented to bind two different antigens independently, while the Fc region is modified to prevent cross-linking, thus resolving the contradiction between multi-antigen targeting and adverse reactions
Solution Approach 2:
Different parts of the antibody are given different properties: the variable regions maintain high binding affinity for multiple antigens, while the Fc region is specifically modified to have reduced cross-linking capability. This local differentiation allows the antibody to achieve multi-antigen targeting without the harmful cross-linking effects
2Reliability
If conventional bispecific antibodies cross-link with FcγR, then they can exert effector functions, but they cannot be administered systemically due to cytokine storms
Solution Approach 1:
The Fc region is modified to exert partial effector functions without full cross-linking capability. This partial action maintains sufficient therapeutic effect while avoiding the excessive cytokine storm response that prevents systemic administration
Solution Approach 2:
Modified Fc regions act as intermediaries that can still engage with FcγR to transmit effector signals, but with altered binding characteristics that prevent the pathological cross-linking and cytokine release syndrome, enabling safe systemic administration
3Adaptability or versatility
If antibodies bind to two different antigens at the same time, then they can achieve bispecificity, but they cannot avoid binding to both antigens simultaneously which causes cross-linking
Solution Approach 1:
The antibody is designed with dynamic binding characteristics where the variable regions can independently bind to two different antigens, but the overall molecular configuration and modified Fc region prevent simultaneous cross-linking of cells, thus achieving bispecificity without harmful cross-linking
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.