Engineered TCR Specificity for KRAS G12V Mutation

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Solution Overview

Problem

Current treatments for KRAS gene mutation-related cancers often inhibit both mutant and wild-type RAS proteins, leading to undesirable side effects and limited efficacy.

Innovation Solution

Development of an engineered T cell receptor (TCR) specific for the KRAS G12>V mutation peptide, which binds to the KRAS G12>V mutation peptide in complex with HLA DRB5*01:01, and is designed to be humanized and soluble, with the option of being covalently bound to therapeutic agents, ensuring specificity and minimizing recognition of wild-type RAS.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments (antibody-drug conjugates, RNA interference) are used to target KRAS mutations, then cancer cells with KRAS mutations can be treated, but wild-type RAS proteins are also inhibited causing unwanted side effects

Engineering Contradiction:

Improvespecificity for mutant KRASVSAvoidside effects from wild-type RAS inhibition

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The TCR is engineered to recognize a specific peptide epitope derived from mutant KRAS (G12V) presented by HLA-DRB5, creating local specificity for the mutation rather than broad inhibition of all RAS proteins. The CDR3 sequences (SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, or 23) are designed to bind specifically to the mutant peptide-MHC complex, distinguishing it from wild-type RAS.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention uses an intermediary approach by targeting the processed peptide epitope as an intermediate form of the mutant KRAS protein, rather than directly inhibiting the RAS protein itself. The TCR recognizes the peptide presented on the cell surface, providing indirect and specific targeting that spares wild-type RAS.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If broad-spectrum RAS inhibitors are used, then all KRAS mutations can be targeted, but treatment specificity decreases and side effects increase

Engineering Contradiction:

Improvecoverage of KRAS mutationsVSAvoidtreatment specificity

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The TCR exhibits local quality through its high specificity for the G12V mutant peptide epitope. The CDR3 regions are engineered to provide precise binding to the mutant peptide-MHC complex, achieving treatment specificity while maintaining adaptability to this particular mutation subtype.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention changes the parameter of target recognition from the protein level (RAS) to the peptide-MHC complex level. This parameter change enables specific recognition of the G12V mutation through the HLA-DRB5-presented peptide epitope, achieving both specificity and mutational coverage for this subtype.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20230399402A1HLA class ii-restricted tcrs against the KRAS g12>v activating mutation

Publication Date: 2023.12.14 LA JOLLA INST FOR IMMUNOLOGY

AI summary

The present invention includes engineered T cell receptor (TCR) proteins, nucleic acids, vectors, host cells, methods of treating cancer, and chimeric antigen receptor expressing T cell (CAR-T) comprising an alpha chain CDR3 having the amino acid sequence of SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, or 23 and/or a beta chain CDR3 having the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24, wherein the TCR is specific for a KRAS G12>V mutation peptide, antigen-MHC binding portions, and full length portions of the same.