Affinity-Optimized Deimmunized CD3 Antibodies for Lower Toxicity
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Solution Overview
Problem
Existing CD3-targeted therapies face dose-limiting toxicity due to off-target T cell activation and immunogenicity issues, including cytokine release syndrome and allergic reactions, primarily caused by murine or humanized antibodies that stimulate T cells and induce immune responses.
Innovation Solution
Development of fully human antibodies with structurally modified CDR regions to reduce immunogenicity and minimize T cell activation, utilizing affinity-optimized and deimmunized variants that minimize binding to HLA proteins, thereby reducing the risk of immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine or humanized antibodies are used to target CD3, then T cell activation and therapeutic effect are achieved, but immunogenicity and dose-limiting toxicity increase
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid sequences in the CDR regions of antibodies. Specifically, it identifies and mutates T cell epitopes that bind to HLA molecules, changing the molecular parameters of the antibody structure to reduce immunogenicity while preserving CD3 binding capability and therapeutic effect
Solution Approach 2:
The patent extracts and removes harmful T cell epitopes from the antibody structure. By identifying specific amino acid sequences in the CDR regions that bind to HLA molecules and cause immunogenicity, the patent removes these epitopes through targeted mutation, separating the harmful immunogenic components from the therapeutic CD3-binding function
2Reliability
If CD3 antibodies are designed to bind strongly to T cells, then therapeutic efficacy improves, but off-target T cell activation and cytokine release syndrome worsen
Solution Approach 1:
The patent applies local quality by making specific localized modifications to the CDR regions where T cell epitopes are located, while leaving other regions of the antibody unchanged. This allows the antibody to maintain strong CD3 binding capability in the antigen-binding site while locally reducing immunogenicity by mutating specific epitopic amino acids that cause off-target activation
Solution Approach 2:
The patent introduces amino acid mutations as intermediaries between the antibody and the immune system. These mutations act as a buffer that prevents direct recognition of the antibody by T cells through HLA presentation, thereby mediating a reduction in immunogenicity without affecting the antibody's primary function of binding CD3 on T cells
Data Source
AI summary
The present invention provides affinity optimized and deimmunized human antibodies that specifically bind to CD3. The present disclosure also provides bispecific antibodies comprising the optimized human antibodies e.g. for activating of T cells. The invention further relates to methods of generating the human antibodies and methods of using them in the treatment of diseases.