Mutated KRAS T Cell Receptors for MHC Class I Cancer Targeting
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Solution Overview
Problem
There is a need for additional treatment options for cancers such as pancreatic, colorectal, lung, endometrial, ovarian, and prostate cancers, particularly when they become metastatic and unresectable, as current treatments like surgery, chemotherapy, and radiation therapy have poor prognosis.
Innovation Solution
Development of isolated or purified T cell receptors (TCRs) with antigenic specificity for mutated KRAS, NRAS, and HRAS epitopes, which can recognize and target cancer cells in a major histocompatibility complex class I-dependent manner, minimizing damage to normal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments (surgery, chemotherapy, radiation therapy) are used for metastatic and unresectable cancers, then treatment coverage is provided, but prognosis remains poor and toxicity to normal cells is high
Solution Approach 1:
The patent uses T cell receptors (TCRs) as intermediaries that specifically recognize mutated KRAS epitopes presented by MHC class I molecules on cancer cells. This intermediary mechanism enables selective targeting of cancer cells while sparing normal cells, resolving the contradiction between effective cancer treatment and reduced toxicity to normal cells
Solution Approach 2:
The patent creates TCRs with localized specificity for mutated epitopes (e.g., KRAS G12D, G12V, G12C mutations) rather than general cancer markers. This local quality approach allows the immune system to distinguish between cancerous and normal cells based on specific molecular characteristics, improving prognosis while minimizing harm to normal tissues
2Measurement precision
If TCRs with high specificity for mutated epitopes are developed, then cancer cell targeting is improved, but complexity of TCR design and production increases
Solution Approach 1:
The patent performs preliminary identification and characterization of mutated epitopes (such as VVVGADGVGK for KRAS G12D) before designing TCRs. This preliminary action includes mapping epitope sequences and validating their presence on cancer cells, which simplifies subsequent TCR design by providing clear targets and reducing trial-and-error complexity
Solution Approach 2:
The patent creates TCR sequences that are copies or variants of naturally occurring T cell receptors that recognize mutated KRAS epitopes. By identifying and replicating functional TCR sequences, the patent achieves high antigenic specificity while avoiding the complexity of de novo TCR design, as these copied TCRs have already been validated by natural selection
Data Source
AI summary
Disclosed is an isolated or purified T cell receptor (TCR) having antigenic specificity for an HLA-A11-restricted epitope of mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) (KRAS7-16), Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog (NRAS), or Harvey Rat Sarcoma Viral Oncogene Homolog (HRAS). Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.