Polypeptide Constructs Targeting J-Configuration CD277

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Solution Overview

Problem

Current immunotherapy approaches for cancer, such as adoptive transfer of T cells with engineered receptors, face challenges in effectively targeting cancer cells due to limitations in recognizing specific configurations of proteins like CD277 associated with disease conditions, particularly the J-configuration formed by RhoB transmigration in distressed cells.

Innovation Solution

A pharmaceutical composition comprising a polypeptide construct that selectively binds the J-configuration of CD277 on cancer cells, combined with agents that increase RhoB GTPase activity or phosphoantigen levels, enhancing the interaction and recognition by γδ T cells, thereby boosting antitumor responses.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If adoptive transfer of T cells with engineered receptors is used, then antitumor specificity is improved, but recognition of specific protein configurations like J-configuration of CD277 is limited

Engineering Contradiction:

Improveantitumor specificityVSAvoidrecognition of protein configurations

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent employs mevalonate pathway inhibitors to alter the metabolic state of cancer cells, specifically increasing phosphoantigen levels and modifying RhoB GTPase activity. These parameter changes induce the J-configuration of CD277 on cancer cell surfaces, making them recognizable by γδ T cells expressing appropriate TCRs, thereby resolving the limitation in configuration recognition while maintaining antitumor specificity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces mevalonate pathway inhibitors as intermediary agents that mediate between the cancer cells and the immune system. These inhibitors modify cancer cell metabolism to produce specific molecular configurations (J-configuration of CD277) that serve as intermediaries for recognition by engineered γδ T cells, bridging the gap between conventional T cell therapy and targetable cancer cell features

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If mevalonate pathway inhibitors are used to increase phosphoantigen levels, then γδ T cell activation is improved, but the mechanism requires understanding of complex metabolic pathways

Engineering Contradiction:

Improveγδ T cell activationVSAvoidmetabolic pathway mechanism

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent extracts and targets a specific metabolic vulnerability in cancer cells by using mevalonate pathway inhibitors. Instead of attempting to control the entire complex metabolic network, the invention focuses on blocking a single key pathway (mevalonate pathway) that leads to accumulation of phosphoantigens and induction of J-configuration CD277, thereby simplifying the therapeutic approach while maintaining reliable γδ T cell activation

Inventive Principle:

Principle #2Taking out (Extraction)

3Reliability

If RhoB GTPase activity is increased to promote J-configuration formation, then CD277 recognition is improved, but translocation and stability control becomes more difficult

Engineering Contradiction:

ImproveCD277 recognitionVSAvoidtranslocation and stability control

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent applies mevalonate pathway inhibitors in advance to cancer cells before immune cell co-culture. This preliminary action modifies the cancer cell metabolic state, pre-forming phosphoantigens and inducing J-configuration of CD277 on the cell surface. By the time γδ T cells are introduced, the target configuration is already in place, eliminating the need for complex real-time control of RhoB translocation and stability during the immune response

Inventive Principle:

Principle #10Preliminary action

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The approach enhances the recognition and targeting of cancer cells by γδ T cells, leading to improved antitumor responses and therapeutic efficacy by leveraging the specific binding of the polypeptide construct to the J-configuration of CD277, which is indicative of distressed cells like cancer cells.

Implementation Method 1

a polypeptide construct that selectively binds the J-configuration of CD277 on cancer cells

Methodology Applied

Scientific EffectSelective binding:

Implementation Method 2

the J-configuration formed by RhoB transmigration in distressed cells

Methodology Applied

Scientific EffectTranslocation:

Implementation Method 3

agents that increase RhoB GTPase activity

Methodology Applied

Scientific EffectGTPase activity:

Implementation Method 4

agents that increase activity of a phosphoantigen in said cancer cell

Methodology Applied

Scientific EffectPhosphoantigen interaction:

Data Source

PatentUS12161669B2Compositions and methods for cell targeting therapies

Publication Date: 2024.12.10 UMC UTRECHT HLDG BV

AI summary

The current disclosure provides polypeptide constructs and cells comprising CDR3 regions of γ9. δ2 or both, that selectively bind a J-configuration of CD277 on a target cell. The disclosure also provides pharmaceutical compositions with the disclosed polypeptides or cells and methods of using these compositions in the treatment of cancer.