Human Anti-CD3 Binding Molecules Resolving Immunogenicity
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Solution Overview
Problem
Current CD3-specific antibodies, such as OKT3, face challenges due to immunogenicity issues in humans, leading to a humoral immune response and reduced efficacy over time, and existing methods like humanization and deimmunization often compromise binding affinity and bioactivity.
Innovation Solution
Development of human binding molecules specifically targeting the extracellular domain of the CD3 ε-chain, selected through affinity-based methods from libraries, ensuring minimal immunogenicity and maintained bioactivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine monoclonal antibodies (e.g., OKT3) are used to target CD3, then potent T cell activation and immunosuppression are achieved, but immunogenicity increases leading to humoral immune response and reduced efficacy over time
Solution Approach 1:
The patent applies parameter changes by modifying the antibody's species origin parameter from murine to human. Humanized anti-CD3 antibodies retain the therapeutic mechanism of murine antibodies while changing the immunogenicity parameter, thereby reducing humoral immune response and improving sustained efficacy in human patients
Solution Approach 2:
The patent uses copying by creating humanized versions of successful murine anti-CD3 antibodies. The variable regions (CDR grafting) that provide target specificity are copied from murine antibodies and inserted into human antibody frameworks, preserving binding function while reducing immunogenicity
2Object-affected harmful factors
If humanization and deimmunization methods are applied to reduce immunogenicity, then immunogenicity decreases, but binding affinity and bioactivity are compromised
Solution Approach 1:
The patent applies local quality by making selective modifications only in specific regions of the antibody molecule. The variable regions containing CDRs are preserved to maintain binding affinity, while only the framework regions are humanized to reduce immunogenicity, thereby achieving local optimization without compromising overall function
Solution Approach 2:
The patent uses partial action by implementing incomplete humanization strategies. Rather than fully humanizing the entire antibody, only portions (framework regions) are humanized while retaining murine CDRs, achieving sufficient immunogenicity reduction while preserving essential binding functions
Data Source
AI summary
The present invention provides a method for the preparation of a human binding molecule, fragment or derivative thereof which specifically binds to the human CD3 complex. Furthermore, the invention provides a human binding molecules specifically binding to the human CD3 complex and means comprising said human binding molecules.