T Cell-Recruiting Polypeptide Complexes With Long Blood Half-Life
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Solution Overview
Problem
Existing cancer treatments using T cell-recruiting antibodies face challenges such as cytokine storms and short blood half-life, limiting their effectiveness and convenience.
Innovation Solution
Development of novel polypeptide complexes with reduced Fc receptor-binding activity and regulated CH1/CL interface association, incorporating Knobs-into-Holes (KiH) modifications, to enhance anti-tumor activity and prolong blood half-life while avoiding cytokine storms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Power
If T cell-recruiting antibodies are administered to enhance anti-tumor activity, then cytotoxic activity against cancer cells is improved, but blood half-life becomes short and cytokine storms occur
Solution Approach 1:
The patent modifies the molecular structure of the T cell-recruiting antibody by altering the Fc region to reduce Fcγ receptor binding activity. This parameter change in the antibody structure extends blood half-life from hours to days while preserving T cell recruitment capability, thereby resolving the contradiction between high cytotoxic activity and short duration of action
Solution Approach 2:
The invention applies local quality modification by specifically targeting the Fc region of the antibody for structural modification while leaving the antigen-binding and CD3-binding regions intact. This localized change reduces FcγR binding in specific areas of the molecule, extending circulation time without compromising the overall anti-tumor mechanism
2Power
If T cell-recruiting antibodies are administered to achieve strong anti-tumor effect, then cytotoxic activity is improved, but harmful side effects such as cytokine storms occur
Solution Approach 1:
By changing the Fc region structure to reduce Fcγ receptor binding affinity, the patent modifies the immunological parameters of the antibody. This parameter change prevents excessive immune activation and cytokine release while maintaining effective T cell recruitment, thereby achieving strong anti-tumor effect without harmful cytokine storms
Solution Approach 2:
The invention converts the potentially harmful FcγR binding activity into a beneficial feature by selectively reducing it. The modified Fc region prevents harmful cytokine storm while the antibody retains its ability to recruit T cells through the CD3 complex, effectively converting a harmful interaction into a controlled, beneficial one
Data Source
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AI summary
By replacing the antigen-binding domain, the present inventors discovered novel polypeptide complexes that retain BiTE's strong anti-tumor activity and excellent safety properties, as well as have long half-life in blood and can damage various different target cells.