Conditionally Active Heterodimeric Polypeptides for Controlled CAR T Cell Activation

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Solution Overview

Problem

Current chimeric antigen receptors (CARs) and engineered T cell receptors (TCRs) used in cell-based adoptive immunotherapy lack pharmacological control, making it difficult to safely modulate immune cell activation, especially when unwanted or excessive activation occurs.

Innovation Solution

Development of conditionally active, heterodimeric polypeptides that consist of a first chimeric polypeptide with a ligand-binding domain (LBD) of a nuclear hormone receptor and a second chimeric polypeptide with a co-regulator, which dimerize in the presence of a dimerization agent to restore enzymatic or signaling activity, allowing for controlled immune cell activation and inhibition.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If CARs and engineered TCRs are used to provide powerful stimulating activity for immune cell activation, then therapeutic efficacy is improved, but pharmacological control and safety are worsened due to inability to modulate activation levels

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidpharmacological control

Core Design Contradiction:

ProductivityVSEase of operation

Solution Approach 1:

The invention divides the antigen receptor into two separate chimeric polypeptides: a first chimeric polypeptide containing the extracellular recognition domain and transmembrane domain, and a second chimeric polypeptide containing the intracellular signaling domain. These segmented polypeptides are expressed as inactive monomers that require dimerization to become functional, thereby enabling pharmacological control through dimerization agents while maintaining therapeutic efficacy when activated.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention introduces dimerization agents as intermediary molecules that mediate the activation of the conditionally active heterodimeric polypeptides. These agents bind to the first and second chimeric polypeptides to induce dimerization, serving as a controllable switch that enables pharmacological modulation of immune cell activation without directly affecting the antigen-binding or signaling functions.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If conditionally active heterodimeric polypeptides are used to enable pharmacological control, then safety and modularity are improved, but device complexity increases due to multiple polypeptide components

Engineering Contradiction:

ImprovesafetyVSAvoidpolypeptide structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention merges multiple functional domains into two chimeric polypeptides: the first chimeric polypeptide combines the extracellular recognition domain with the transmembrane domain, and the second chimeric polypeptide combines the intracellular signaling domain with a dimerization domain. This merging strategy reduces the number of separate components compared to traditional multi-domain CAR structures while enabling conditional activation through controlled dimerization.

Inventive Principle:

Principle #5Merging (Combining)

3Ease of operation

If dimerization-induced activation mechanism is implemented, then pharmacological control is improved, but manufacturing complexity increases due to expression of multiple polypeptides

Engineering Contradiction:

Improvepharmacological controlVSAvoidpolypeptide expression

Core Design Contradiction:

Ease of operationVSEase of manufacture

Solution Approach 1:

The invention creates a dynamic system where the antigen receptor functionality is not fixed but can be switched on and off through dimerization. The first and second chimeric polypeptides are expressed as inactive monomers under physiological conditions, and activation is dynamically controlled by the presence or absence of dimerization agents, allowing flexible pharmacological modulation throughout the therapeutic process.

Inventive Principle:

Principle #15Dynamics

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

Enables precise modulation of immune cell activity, allowing for controlled activation or inhibition, thereby enhancing the safety and efficacy of immunotherapy by using a dimerization-induced activation mechanism.

Implementation Method 1

the first member of the dimerization pair comprises a ligand-binding domain (LBD) of a nuclear hormone receptor... wherein the first chimeric polypeptide and the second chimeric polypeptide are dimerized in the presence of a dimerization agent that induces binding of the LBD to the co-regulator

Methodology Applied

Scientific EffectLigand binding: Absorption (physical)

Data Source

PatentUS11136562B2Conditionally active heterodimeric polypeptides and methods of use thereof

Publication Date: 2021.10.05 RGT UNIV OF CALIFORNIA

AI summary

The present disclosure provides conditionally active, heterodimeric polypeptides. The conditionally active, heterodimeric polypeptides are active in the presence of a dimerizing agent that induces dimerization of the polypeptides of the heterodimer. A conditionally active, heterodimeric polypeptide of the present disclosure is useful in a variety of research and treatment methods, which are also provided.