Radium-1 TCR targeting frameshift mutant TGFβRII
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current adoptive cell transfer therapies for cancer using T-cell receptors (TCRs) face challenges such as severe toxicity due to cross-reactivity and MHC limitation, and the lack of effective TCRs targeting frameshift mutations in TGFβRII, which are common in MSI+ colorectal cancers.
Innovation Solution
Development of a TCR molecule, Radium-1, specifically targeting the frameshift mutation-derived neopeptide RLSSCVPVA in TGFβRII, which is HLA-A2 restricted and can be expressed by both CD4+ and CD8+ T-cells, allowing for high affinity binding to the cognate antigen/MHC complex without requiring co-receptor interaction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional TCRs are used in adoptive cell transfer therapy, then T-cells can recognize cancer antigens, but severe toxicity occurs due to cross-reactivity with normal tissues
Solution Approach 1:
The TCR is designed to recognize a highly specific local sequence (RLSSCVPVA) within the TGFβRII protein that is only present in the mutated form in cancer cells. This local specificity at the amino acid sequence level allows discrimination between mutated and wild-type proteins, enabling tumor-targeted killing without cross-reactivity against normal tissues expressing the wild-type TGFβRII receptor.
2Adaptability or versatility
If TCRs are designed to target common cancer mutations, then broader applicability is achieved, but MHC limitation restricts patient eligibility
Solution Approach 1:
The TCR is designed to recognize a mutation that occurs in approximately 90% of MSI+ colorectal cancers, giving it broad applicability across this patient population. While the TCR is HLA-A2 restricted, this approach provides a universal solution for HLA-A2 positive patients with MSI+ cancers, and multiple TCRs can be developed for different HLA types to achieve population-wide coverage.
3Adaptability or versatility
If TCR therapy is expanded to target more cancer types, then treatment options increase, but off-target effects and autoimmune reactions increase
Solution Approach 1:
The invention converts the typically harmful frameshift mutation, which causes cancer through loss of TGFβ signaling, into a beneficial target for immunotherapy. The mutation creates a unique neoepitope that is absent from normal tissues, allowing the TCR to selectively target cancer cells without affecting normal physiology. The harmful mutation becomes a unique identifier that enables precise cancer cell recognition and destruction.
4Productivity
If high-affinity TCRs are developed to improve killing efficiency, then tumor cell lysis increases, but cross-reactivity and toxicity also increase
Solution Approach 1:
The TCR achieves high affinity binding (Kd in the low nanomolar range) specifically to the mutated RLSSCVPVA sequence presented by HLA-A2, while maintaining selectivity that prevents cross-reactivity with wild-type TGFβRII or other proteins. The local amino acid sequence differences in the neoepitope provide sufficient binding energy for high affinity while ensuring specificity through precise molecular recognition of the mutated sequence.
Data Source
Figure 1A~1C
Figure 2~3
Figure 4~5
AI summary
The present invention relates to TCR molecules which recognise neopeptides produced as a result of the cancer-associated "-1A" frameshift mutation in human TGFβRII. The TCR molecules are capable of binding a peptide of SEQ ID NO: 1 when said peptide is presented by a Class I MHC, and comprise an α-chain domain and a β-chain domain, each chain domain comprising three CDR sequences, wherein a) CDRs 1, 2 and 3 of the α-chain domain have the sequences of SEQ ID NOs: 2, 3 and 4 respectively; and b) CDRs 1, 2 and 3 of the β-chain domain have the sequences of SEQ ID NOs: 5, 6 and 7 respectively, and wherein one or more of said CDR sequences may optionally be modified by substitution, addition or deletion of 1 or 2 amino acids. Nucleic acid molecules encoding such TCRs are provided, as are soluble TCR molecules with these CDR sequences. The nucleic acid molecules of the invention can be used to modify immune effector cells to express a TCR as defined herein, and such modified immune effector cells are useful in therapy for cancer, as are soluble TCRs as defined above.