Mutated p53 T-Cell Receptors for HLA-A2 Cancer Targeting
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Solution Overview
Problem
There is an unmet need for additional treatments for cancers, particularly those that are metastatic and unresectable, as existing treatments like surgery, chemotherapy, and radiation therapy often provide poor prognosis for cancers such as pancreatic, colorectal, lung, endometrial, ovarian, and prostate cancers.
Innovation Solution
Development of isolated or purified T cell receptors (TCRs) with antigenic specificity for mutated human p53, specifically targeting the R175H mutation presented by HLA-A2, comprising defined CDR sequences, which can be used to detect and treat cancer by recognizing mutated p53 in an HLA-molecule-dependent manner.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional treatments (surgery, chemotherapy, radiation therapy) are used for metastatic and unresectable cancers, then treatment options are limited, but prognosis remains poor
Solution Approach 1:
The patent changes the fundamental parameter of cancer treatment from conventional non-specific therapies to targeted immunotherapy. By designing T cell receptors with specific antigenic specificity for mutated p53 peptides presented by HLA-A2, the treatment transitions to a precision medicine approach that targets molecular characteristics rather than using broad-spectrum conventional therapies.
Solution Approach 2:
The patent introduces T cell receptors as intermediary elements between the patient's immune system and cancer cells. These engineered TCRs act as mediators that recognize mutated p53 peptides presented by HLA-A2 molecules on cancer cell surfaces, enabling the immune system to specifically target and destroy cancer cells with mutated p53 while sparing normal cells.
2Reliability
If T cell receptors with specific antigenic specificity for mutated p53 are designed, then cancer cells expressing mutated p53 can be selectively targeted, but the complexity of TCR structure and sequence definition increases
Solution Approach 1:
The patent segments the T cell receptor into distinct functional components: the alpha chain with specific CDR sequences (CDR1, CDR2, CDR3) and the beta chain with corresponding CDR sequences. This segmentation allows independent optimization and definition of each chain's contribution to antigen recognition, making the complex TCR structure more manageable and reproducible.
Solution Approach 2:
The patent applies local quality by defining specific complementarity determining region (CDR) sequences in the TCR alpha and beta chains that are responsible for recognizing mutated p53 peptides. By identifying and specifying the exact amino acid sequences in these local regions (CDR1, CDR2, CDR3 of each chain), the patent achieves high selectivity for cancer cells with mutated p53 while maintaining manageable overall structure.
3Productivity
If T cell receptors recognizing mutated p53 are developed, then cancer cells can be destroyed with high avidity, but the risk of off-target effects on normal cells increases
Solution Approach 1:
The patent extracts the targeting function from conventional non-specific cancer therapies and concentrates it into the T cell receptor's antigen recognition capability. By isolating and defining the specific CDR sequences that recognize mutated p53 peptides, the TCR achieves high productivity in cancer cell destruction while the specificity of this extracted targeting function minimizes off-target effects on normal cells.
Solution Approach 2:
The patent employs a disposable, highly specific T cell receptor design that can be rapidly produced and administered. The TCR's temporary presence in the patient's system allows for rapid cancer cell targeting without long-term commitment to complex treatment protocols, and the high specificity ensures that even transient exposure does not cause significant off-target damage to normal cells.
Data Source
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AI summary
Disclosed is an isolated or purified T cell receptor (TCR) having antigenic specificity for mutated human p53. 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.