Engineered T Cells Targeting ROPN1 Epitopes for Solid Tumors
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Solution Overview
Problem
Current adoptive T cell therapies face challenges in treating solid tumors due to issues like on-target and off-target toxicities, heterogenous expression of target antigens, and limited research into intracellular antigens, leading to suboptimal efficacy and safety concerns.
Innovation Solution
Engineered T cells are developed to express T cell receptors or antibody-based receptors with specificity to tumor-selective and immunogenic epitopes of human ropporin-1A and ropporin-1B, which are frequently and homogenously expressed in certain cancer types, such as breast and skin cancers, and hematological malignancies, to enhance tumor targeting while minimizing toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used to treat solid tumors, then tumor targeting capability is improved, but treatment-related toxicities (on-target and off-target) worsen
Solution Approach 1:
The patent applies local quality by engineering T cells to express multiple TCRs with different specificities (e.g., TCR1 specific for epitope 1, TCR2 specific for epitope 2) rather than a single uniform receptor. This allows different regions of the tumor (with different antigen expression patterns) to be targeted while reducing toxicity through epitope spreading - the T cell product attacks multiple distinct epitopes rather than a single target, distributing the immune response across multiple antigens and reducing on-target toxicity.
Solution Approach 2:
The patent changes the parameter of receptor specificity by using TCRs that recognize intracellular antigens presented by MHC molecules rather than extracellular antigens. This fundamental parameter change enables targeting of intracellular tumor antigens that are not accessible to CAR T cells, expanding the targetable antigen space while maintaining tumor specificity through MHC-restricted recognition.
2Adaptability or versatility
If TCR-engineered T cells target intracellular antigens, then target coverage is improved (100% of targets), but treatment-related toxicities worsen due to off-target recognition
Solution Approach 1:
The patent segments the target antigen into multiple distinct epitopes (epitope 1, epitope 2, etc.) and engineers T cells to express multiple TCRs each specific for a different epitope. This segmentation approach allows the immune system to target multiple discrete regions of the tumor antigen, providing broader coverage while reducing the risk of off-target toxicity by distributing recognition across multiple epitope-specific receptors rather than relying on a single high-affinity TCR that might cross-react with normal tissues.
Solution Approach 2:
The patent uses MHC molecules as intermediaries between intracellular tumor antigens and TCR-engineered T cells. The MHC molecule presents processed peptide fragments of intracellular antigens on the cell surface, allowing TCRs to recognize intracellular targets without directly contacting the bulk intracellular antigen. This intermediary mechanism enables targeted recognition of tumor-specific intracellular antigens while reducing off-target effects, as the TCR-MHC-peptide complex interaction is highly specific and can be engineered to recognize tumor-restricted antigens.
3Productivity
If affinity-enhanced TCRs are used to improve tumor recognition, then tumor cell killing efficacy is improved, but off-target toxicities worsen
Solution Approach 1:
The patent applies dynamics by combining TCRs with different affinity characteristics in a single T cell product. Rather than using uniformly high-affinity TCRs that might cause off-target toxicity, the invention uses a mixture of TCRs with varying affinities for their respective epitopes. This dynamic approach allows the T cell product to engage tumor cells through multiple low-to-moderate affinity interactions, achieving effective tumor cell killing through cumulative effect while reducing the risk of any single high-affinity TCR causing off-target toxicity.
Data Source
AI summary
The invention provides inter alia an engineered T cell, wherein said T cell is engineered to express a T cell receptor (TCR) or an antibody-based receptor that binds to a T cell epitope of human ropporin-1A (ROPN1) or human ropporin-1B (ROPN1B); wherein said T cell epitope is selected from the group consisting of SEQ ID NO:4, SEQ ID NO:43, SEQ ID NO:23, SEQ ID NO:56 and SEQ ID NO:24.