BTN2-BTN3 Heteromeric Complex for Phosphoantigen-Independent TCR Activation

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Solution Overview

Problem

There is a need to better understand the mechanisms governing phosphoantigen recognition to develop novel immunotherapies that can induce γδ T cell responses in cancer patients, patients with chronic infections, or those with autoimmune or inflammatory diseases.

Innovation Solution

The development of a recombinant BTN2-BTN3 heteromeric complex that binds to Vγ9Vδ2+ TCR, enhancing γδ T cell-mediated immunity, along with modified BTN2 and BTN3 that can interact with Vγ9Vδ2+ TCR independently of phosphoantigens.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If BTN2 and BTN3 are used separately, then they can be produced and purified individually, but they cannot effectively activate Vγ9Vδ2+ T cells without phosphoantigen

Engineering Contradiction:

ImproveT cell activation capabilityVSAvoidcomplex structure requirement

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent combines BTN2 and BTN3 into a heteromeric complex where BTN2 forms a homodimer and BTN3 forms a homodimer, creating a quaternary structure that can activate Vγ9Vδ2+ T cells independently of phosphoantigen. This merging of separate protein functions into a single complex resolves the contradiction by enabling T cell activation while maintaining producibility of individual components.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The heteromeric complex acts as an intermediary between the separate BTN proteins and the T cell receptor, facilitating activation without requiring phosphoantigen. The complex structure with specific orientation and spacing of BTN2 and BTN3 domains creates a novel activation mechanism that bypasses the need for traditional phosphoantigen recognition.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If phosphoantigen is used to activate γδ T cells, then specific immune responses are triggered, but the mechanism is limited to peptide-MHC recognition pathways

Engineering Contradiction:

Improveimmune response inductionVSAvoidrecognition mechanism complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

Instead of using phosphoantigen to activate T cells through the traditional TCR-pMHC pathway, the patent inverts the approach by using a engineered BTN2-BTN3 complex that directly engages the TCR in a phosphoantigen-independent manner. This inversion creates a new activation pathway that is not constrained by traditional antigen presentation mechanisms.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The heteromeric complex serves multiple functions: it maintains the structural features of individual BTN proteins while acquiring new T cell activating capability independent of phosphoantigen. The complex can potentially interact with multiple TCR variants and serves both as a structural scaffold and an activation trigger, demonstrating multi-functionality.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20250179144A1Modified Butyrophilin and Butyrophilin Complexes

Publication Date: 2025.06.05 UNIVERSITY OF MELBOURNE

AI summary

The present disclosure relates to modified butyrophilin 2A and 3A, and butyrophilin 2A-3A complexes and use thereof to induce or enhance TCR activation.