Valency Controllable Receptor Systems for CAR T Cell Therapy

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Solution Overview

Problem

Current CAR T cell therapies require high target antigen density and lack control over engineered immune cell activity, leading to inefficiencies in cancer treatment due to tumor escape, cytokine release syndrome, and off-tumor targeting, especially in solid tumors and autoimmune diseases.

Innovation Solution

Development of valency controllable receptor polypeptides and systems that include an extramembrane signal recognition domain, a valency controller module, and intramembrane signaling domains, allowing for oligomerization upon custom input recognition, enhancing antigen recognition and signaling pathways for improved therapeutic control and efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR T cell therapy is used to target cancer cells, then immune response against cancer is improved, but tumor escape occurs due to low antigen density

Engineering Contradiction:

Improveimmune response effectivenessVSAvoidantigen density

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent changes the parameter of receptor valency from fixed (natural 1:1 binding) to controllable (tunable oligomeric states). By using valency controllable receptor polypeptides that can be switched between monomeric and oligomeric states via protease cleavage, the system adapts to different antigen density conditions, maintaining effective immune response whether antigen density is high or low.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces dynamic control over receptor valency through protease-cleavable linkers. The receptor polypeptides transition from a controlled (monomeric) state to an active (oligomeric) state upon protease cleavage, allowing the system to dynamically adapt its binding characteristics based on therapeutic needs and antigen availability.

Inventive Principle:

Principle #15Dynamics

2Reliability

If engineered immune cells are activated autonomously, then cancer targeting is improved, but cytokine release syndrome and T cell exhaustion occur

Engineering Contradiction:

Improvecancer targeting efficacyVSAvoidcytokine release syndrome

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces a controllable intermediary mechanism (valency controller module with protease-cleavable linkers) that mediates between the engineered receptor and its target. This intermediary allows external control over receptor activation timing and intensity, preventing uncontrolled autonomous activation and its harmful consequences while maintaining effective cancer targeting when properly regulated.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The system enables feedback control through the valency controller module, where protease activity (which can be regulated) controls the transition from monomeric to oligomeric receptor states. This creates a controllable feedback loop that prevents overactivation and associated harmful effects while maintaining therapeutic efficacy.

Inventive Principle:

Principle #23Feedback

3Measurement precision

If T cells are engineered with high specificity for disease antigens, then cancer targeting is improved, but off-tumor targeting occurs due to low specificity of T cell spatial localization

Engineering Contradiction:

Improveantigen recognition specificityVSAvoidoff-tumor targeting

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent changes the parameter of receptor valency to control binding affinity and specificity. By adjusting the oligomeric state of the receptor (monomer vs. oligomer), the system can fine-tune its binding characteristics to achieve high specificity for tumor antigens while minimizing off-tumor targeting, as the controllable valency allows optimization of the balance between affinity and specificity.

Inventive Principle:

Principle #35Parameter changes

4Adaptability or versatility

If multiple signaling pathways are activated in T cells, then immune response diversity is improved, but current CAR designs are limited to single pathway activation

Engineering Contradiction:

Improvesignaling pathway diversityVSAvoidCAR design complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent creates a universal platform (valency controllable receptor system) that can be applied to multiple different extramembrane signal recognition domains and intramembrane signaling domains. This multi-functional framework allows a single controllable valency mechanism to work with various signaling pathways, achieving pathway diversity without proportionally increasing overall system complexity.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20250017960A1Composition and method of valency controlled receptor systems for cell engineering and therapy

Publication Date: 2025.01.16 THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV

AI summary

Provided herein are valency controllable receptor polypeptides configured to oligomerize upon recognition of a custom input. The receptors include an extramembrane signal recognition domain configured to recognize an extramembrane signal different from the custom input, a valency control module configured to recognize the custom input and induce oligomerization of the polypeptide, and an intramembrane signaling domain configured to modulate one or more intramembrane pathways. The provided receptors are particularly useful for engineered cell therapies. Also provided are systems and host cells including the disclosed receptors, and methods for using the disclosed materials.