Bispecific T-Cell Modulatory Polypeptides for Reduced Immune Toxicity
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Solution Overview
Problem
Current methods for modulating T-cell activity are limited in specificity and efficacy, often leading to adverse immune responses and requiring high doses of antibodies like anti-CTLA4, which can cause immune-related adverse events.
Innovation Solution
Development of T-cell modulatory multimeric polypeptides comprising two different immunomodulatory polypeptides, including variant polypeptides with reduced binding affinity to specific co-immunomodulatory proteins, to enhance target cell specificity and reduce adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high doses of anti-CTLA4 antibodies are used to modulate T-cell activity, then T-cell activation is enhanced, but immune-related adverse events increase
Solution Approach 1:
The invention divides the single antibody therapy into a bispecific antibody that targets two different antigens (CD3 and CTLA-4), segmenting the immune modulation function into distinct binding domains that work协同 to achieve T-cell activation with reduced adverse effects
Solution Approach 2:
The bispecific antibody exhibits different binding affinities and functional properties at different binding sites - the CD3 binding domain provides T-cell engagement while the CTLA-4 binding domain provides costimulatory signaling, with each domain optimized for its specific function to reduce adverse events
2Reliability
If conventional immunomodulatory antibodies are used, then T-cell activity is modulated, but specificity is limited leading to adverse immune responses
Solution Approach 1:
The antibody is segmented into two distinct antigen-binding domains with different specificities (CD3 and CTLA-4), allowing simultaneous engagement of multiple targets to achieve precise T-cell modulation while avoiding off-target effects
Solution Approach 2:
The bispecific antibody functions as a composite immunomodulatory agent combining properties of both anti-CD3 and anti-CTLA-4 antibodies, creating a new therapeutic entity with enhanced specificity and reduced adverse immune responses
Data Source
AI summary
The present disclosure provides T-cell modulatory multimeric polypeptides comprising two different immunomodulatory polypeptides, at least one of which is a variant immunomodulatory polypeptide. The present disclosure provides nucleic acids comprising nucleotide sequences encoding the T-cell modulatory multimeric polypeptides, and host cells comprising the nucleic acids. The present disclosure provides methods of modulating the activity of a T cell; the methods comprise contacting the T cell with a T-cell modulatory multimeric polypeptide of the present disclosure.