Defined CDR3 TCR Binding Polypeptides for MHC-I Glioma Targeting

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Solution Overview

Problem

Existing cancer treatments, such as adoptive T cell therapy and TIL therapy, face challenges in effectively targeting intracellular tumor-associated antigens (TAAs) and maintaining T cell responses against solid tumors, particularly gliomas with low mutational burden.

Innovation Solution

Development of a binding polypeptide comprising a first and second variable T cell receptor (TCR) domain with specific CDR3 sequences, designed to target cancer cells expressing PTPRZ1 and/or NLGN4X, presented on MHC class I molecules, for enhanced T cell therapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If TIL therapy is used to amplify spontaneous T cell responses ex vivo, then T cell responses can be enhanced, but unspecific cytokine-driven in vitro expansion leads to loss of potentially TAA-reactive T cell clones

Engineering Contradiction:

ImproveT cell response magnitudeVSAvoidTAA-reactive T cell clone retention

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent introduces a specific TCR as an intermediary that mediates targeted recognition of TAAs. Instead of relying on unspecific cytokine-driven expansion, the TCR-transgenic T cells provide a specific mediator (the TCR with defined CDR3 sequences) that enables selective amplification and retention of TAA-reactive clones, resolving the contradiction between enhancing response magnitude and preserving reactive clone diversity

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the specificity parameter of T cell therapy by engineering T cells with defined TCR sequences (specific CDR3 amino acid sequences). This parameter change transforms non-specific T cell expansion into specific TAA-targeted expansion, allowing productivity enhancement while maintaining reliability through precise antigen recognition

Inventive Principle:

Principle #35Parameter changes

2Productivity

If CAR therapy is used to target cell surface antigens, then remarkable regressions can be achieved in leukemia and lymphoma, but translation to solid tumors proves difficult due to identification of suitable cell surface antigens

Engineering Contradiction:

Improvetumor regression efficacyVSAvoidapplicability to solid tumors

Core Design Contradiction:

ProductivityVSAdaptability or versatility

Solution Approach 1:

The patent inverts the approach by moving from cell surface antigen targeting (CAR) to intracellular antigen targeting (TCR). Instead of searching for suitable surface antigens on solid tumors, the invention uses TCR to directly recognize intracellular TAAs that are processed and presented on MHC molecules, enabling solid tumor targeting where CAR therapy fails

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent introduces MHC-presented peptide antigens as intermediaries between intracellular TAAs and T cell recognition. The TCR serves as a mediator that recognizes the peptide-MHC complex, bridging the gap between intracellular tumor antigens and immune recognition, thereby enabling solid tumor targeting

Inventive Principle:

Principle #24Intermediary (Mediator)

3Productivity

If therapeutic vaccinations are used to induce T cell responses against TAAs, then T cell responses can be amplified, but the level of cellular effector immune responses required to control tumor growth is not achieved

Engineering Contradiction:

ImproveT cell response levelVSAvoidtumor growth control efficacy

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the specificity and potency parameters by using TCR-transgenic T cells with defined CDR3 sequences that specifically recognize TAAs. This creates a more potent and reliable effector response compared to therapeutic vaccinations, achieving the necessary response level to control tumor growth while maintaining high specificity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent performs preliminary action by pre-engineering T cells with specific TCR sequences before infusion. This preliminary configuration ensures that the T cells are pre-programmed to recognize and effectively respond to tumor antigens, achieving the required effector response level from the outset rather than relying on vaccination-induced responses

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS20250277013A1T cell receptor derived binding polypeptides

Publication Date: 2025.09.04 DEUTES KREBSFORSCHUNGSZENT STIFTUNG DES OFFENTLICHEN RECHTS

AI summary

The present invention relates to a binding polypeptide comprising a first variable T cell receptor (TCR) domain and a second variable TCR domain wherein (i) the complementarity determining region 3 (CDR3) of the first variable TCR domain comprises, preferably consists of, the amino acid sequence of SEQ ID NO: 1 or a sequence at least 80% identical thereto; and/or wherein the CDR3 of the second variable TCR domain comprises, preferably consists of, the amino acid sequence of SEQ ID NO:2 or a sequence at least 80% identical thereto; or wherein (ii) the CDR3 of the first variable TCR domain comprises, preferably consists of, the amino acid sequence of SEQ ID NO:3 or a sequence at least 80% identical thereto; and/or wherein the CDR3 of the second variable TCR domain comprises, preferably consists of, the amino acid sequence of SEQ ID NO:4 or a sequence at least 80% identical thereto; and to polynucleotides, host cells, methods, uses, kits, and devices related thereto.