Tri-Specific T Cell Binding Proteins for Low-Toxicity CD8+ Targeting
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Solution Overview
Problem
Existing T cell engagers face challenges with high cytokine release syndrome (CRS), neurotoxicity, short half-life, and off-target activation of regulatory T cells, limiting their efficacy in cancer treatment.
Innovation Solution
Development of binding proteins with specific structures comprising tumor-associated antigen, T cell receptor, and T cell co-stimulatory molecule binding sites, designed to preferentially engage CD8+ T cells, reducing off-target effects and activating CD8+ T cells for targeted tumor cell destruction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high affinity-CD3 binding domains are used to induce T cell activation, then potent T cell activation is achieved, but cytokine release syndrome and neurotoxicity increase
Solution Approach 1:
The patent applies local quality by making the CD3 binding domain affinity selective rather than uniformly high. The engineered CD3 binding domain exhibits reduced affinity compared to conventional high affinity domains, which locally modifies the interaction strength to reduce off-target effects while maintaining sufficient T cell activation capability. This selective affinity adjustment resolves the contradiction between activation potency and toxicity reduction.
2Adaptability or versatility
If CD3-based T cell engagers are designed to activate both CD4 and CD8 T cells, then broad T cell engagement is achieved, but regulatory T cell activation increases which decreases cytolytic activity
Solution Approach 1:
The patent applies local quality by making the T cell engagement selective for specific T cell subsets. The engineered binding protein preferentially engages CD8+ T cells while avoiding regulatory T cell activation, which locally modifies the engagement pattern to enhance cytolytic activity. This selective subset engagement resolves the contradiction between broad engagement and cytolytic efficacy.
3Device complexity
If simple bispecific T cell engager format is used, then manufacturability is poor and half-life is short, but structural complexity is reduced
Solution Approach 1:
The patent applies composite materials by combining different molecular domains into a engineered binding protein structure. The molecule comprises a Fc region combined with CD3 binding domains and tumor antigen binding domains, creating a composite structure that leverages the long half-life and effector functions of the Fc region while maintaining bispecific engagement capability. This composite structure resolves the contradiction between simplicity and half-life.
Data Source
AI summary
The disclosure generally relates to binding proteins that comprise antigen binding sites, a T cell receptor binding site, and a T cell co-stimulatory molecule binding site. The disclosure also provides compositions comprising such binding proteins and nucleic acid molecules encoding such binding proteins. The disclosure further relates to methods of treating a disorder or condition using such binding proteins.