Bivalent Fab T-Cell Engager for pMHC Targeting
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Solution Overview
Problem
Current immunotherapies targeting peptide-MHC complexes on cancer cells face challenges due to low affinity and specificity of naturally occurring TCRs, requiring significant engineering efforts that may compromise specificity, and existing antibody molecules with high affinity often have unwanted Fc-mediated immune functions leading to cytokine release syndrome and T cell exhaustion.
Innovation Solution
Development of antigen binding proteins in a Fab format that specifically bind to peptide-MHC complexes with bivalent targeting and lack an Fc domain, utilizing a Fab domain as a scaffold with linked pMHC binding domains to enhance cancer cell killing while minimizing nonspecific activation and toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naturally occurring TCRs are used to target pMHC complexes, then the system is simple and retains natural specificity, but the binding affinity is too low (0.1-500 μM) to be effective as a drug
Solution Approach 1:
The patent creates soluble antibody molecules that copy and mimic the structure and function of naturally occurring TCRs. These engineered antibodies replicate the pMHC recognition capability while achieving drug-level stability and affinity, eliminating the need for complex TCR engineering while maintaining natural specificity
Solution Approach 2:
The patent modifies key parameters of TCR-like molecules by engineering them as soluble antibodies with optimized stability and affinity characteristics. This transforms naturally occurring TCRs with micromolar affinity into therapeutic candidates with nanomolar affinity and enhanced biophysical properties suitable for drug development
2Reliability
If high-affinity soluble antibody molecules are developed to target pMHCs, then binding affinity and specificity are improved, but the development process requires significant engineering efforts that may compromise specificity
Solution Approach 1:
The patent uses naturally occurring cancer-reactive TCRs as templates, copying their antigen-specific recognition properties. This approach preserves the inherent specificity of naturally selected TCRs while engineering them into stable soluble antibody formats, avoiding de novo design challenges that could compromise specificity
3Duration of action of stationary object
If Fc-containing antigen binding proteins are used, then half-life is extended, but this leads to increased toxicity from excess cytokine release and T cell exhaustion
Solution Approach 1:
The patent extracts only the essential antigen-binding and T-cell engagement functions by using Fab fragments without the Fc domain. This removal eliminates Fc-mediated immune activation and cytokine release while retaining the core therapeutic mechanism of T-cell redirected killing, achieving toxicity reduction without sacrificing efficacy
4Object-generated harmful factors
If monovalent bispecific T-cell engagers are used, then Fc-mediated immune functions are avoided, but cancer cell killing efficiency is reduced compared to bivalent formats
Solution Approach 1:
The patent employs asymmetric valency distribution with two pMHC-binding domains and one CD3-binding domain in the Fab fragment. This asymmetric configuration enables bivalent engagement of tumor antigens for enhanced killing efficiency while maintaining monovalent CD3 engagement to avoid Fc-mediated toxicity, achieving both goals simultaneously
Data Source
AI summary
Described herein are antigen binding proteins comprising a Fab domain which specifically binds to a cell surface protein of an immune cell, a first pMHC binding domain, and a second pMHC binding domain. Methods of treating cancer or a viral infection with the same are also described.