PD-L1/2 Targeting Module for Switchable CAR-T Therapy

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Solution Overview

Problem

Conventional chimeric antigen receptor (CAR) technology faces challenges such as uncontrolled immune responses, tumor escape variants, and toxicity issues, particularly when targeting solid tumors with inhibitory immune checkpoints like PD-L1 or PD-L2, which limits its broad applicability and efficacy.

Innovation Solution

A targeting module comprising a PD-L1 and/or PD-L2 binding domain and a tag-binding domain is used in combination with a switchable chimeric antigen receptor, allowing for specific targeting of tumor cells and a reversible immune response, with a short pharmacokinetic and pharmacodynamic half-life to minimize toxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CAR technology is used to target tumor cells, then anti-tumor immune response is activated, but uncontrolled immune response and toxicity occur

Engineering Contradiction:

Improveanti-tumor immune responseVSAvoidtoxicity to normal cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The CAR system is divided into two separate components: a universal CAR that recognizes a tag (e.g., GCN4) and a targeting module that contains the antigen-specific binding domain. The targeting module is administered separately and temporarily, allowing control over when and where the immune response is activated. This segmentation enables the immune response to be triggered only when both components are present at the target site, reducing off-target toxicity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The system employs dynamic control through the temporary administration of the targeting module. The immune response can be switched on by administering the targeting module and switched off by withholding it, as the universal CAR remains expressed but inactive without the targeting module. This dynamic approach allows flexible control over the duration and intensity of the immune response, reducing cumulative toxicity.

Inventive Principle:

Principle #15Dynamics

2Productivity

If CAR-T cells are infused to treat cancer, then tumor killing is achieved, but tumor lysis syndrome and cytokine release syndrome occur

Engineering Contradiction:

Improvetumor cell killingVSAvoidcytokine release syndrome

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The universal CAR is pre-expressed in the immune cells before treatment, but the actual anti-tumor activity is postponed until the targeting module is administered. This preliminary preparation allows the immune cells to be ready for action without being activated prematurely, enabling controlled initiation of tumor cell killing and reducing uncontrolled cytokine release.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The targeting module is administered in controlled doses and intervals, enabling periodic activation of the immune response. This allows tumor cell killing to occur in controlled waves rather than continuously, giving the patient's system time to recover and reducing the severity of cytokine release syndrome between treatment cycles.

Inventive Principle:

Principle #19Periodic action

3Duration of action of stationary object

If conventional CAR-T cells are used, then long-term immune response is maintained, but difficulty in controlling and switching off the response occurs

Engineering Contradiction:

Improveduration of immune responseVSAvoidcontrollability of immune response

Core Design Contradiction:

Duration of action of stationary objectVSEase of operation

Solution Approach 1:

The targeting module acts as an intermediary that temporarily bridges the universal CAR and the tumor antigen. By controlling the administration and dosage of this intermediary component, the duration and intensity of the immune response can be precisely regulated. The response lasts as long as the targeting module is present in sufficient quantities, providing easy on/off control.

Inventive Principle:

Principle #24Intermediary (Mediator)

4Measurement precision

If CAR technology targets a single antigen, then focused immune response is achieved, but tumor escape variants develop

Engineering Contradiction:

Improveantigen specificityVSAvoidprotection against tumor escape

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The universal CAR component can recognize any tag, allowing the system to be retargeted to different antigens by simply changing the targeting module. This multi-functionality enables the treatment of tumors expressing different antigens and reduces the risk of escape variants, as the same universal CAR platform can be redirected to target alternative antigens if resistance develops.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20230183351A1A targeting module comprising PD-l1 and/or PD-l2 for use in a method for stimulating a chimeric antigen receptor mediated immune response in a mammal

Publication Date: 2023.06.15 AVENCELL EUROPE GMBH

AI summary

The present invention relates to a targeting module comprising at least one PD-L1 and/or PD-L2 binding domain, and a tag-binding domain or a tag for use in a method for stimulating a chimeric antigen receptor mediated immune response in a mammal, a nucleic acid, a vector or a cell comprising a nucleotide sequence encoding the targeting module, a pharmaceutical composition and a kit comprising the targeting module and a vector or a cell comprising a nucleotide sequence encoding a switchable chimeric antigen receptor.