Chimeric Transmembrane Proteins for Antigen-Independent CAR T-Cell Activation

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Solution Overview

Problem

Existing chimeric antigen receptor (CAR) T-cells lack sufficient antigen-independent co-stimulatory activity, particularly in solid tumors with low tumor-associated antigen levels, and prolonged administration of recombinant cytokines like IL-2 is associated with severe side effects.

Innovation Solution

Development of chimeric transmembrane proteins incorporating an extracellular IL-2 domain, an extracellular sushi domain of an alpha chain of the interleukin-2 receptor, and a transmembrane domain to provide antigen-independent co-stimulation for CAR T-cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If recombinant cytokines like IL-2 are administered to provide co-stimulatory activity to CAR T-cells, then T-cell proliferation and activation are enhanced, but severe side effects occur that limit duration and dosage

Engineering Contradiction:

ImproveT-cell proliferationVSAvoidside effects

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces an intermediary molecule (IL-2 domain fused to Fc region) that acts as a soluble receptor to capture and present endogenous IL-2 to CAR T-cells. This mediator enables indirect co-stimulation without direct administration of high doses of recombinant IL-2, thereby reducing side effects while maintaining T-cell proliferation and activation.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention enables CAR T-cells to utilize endogenous IL-2 produced by the patient's own cells through the IL-2/Fc complex formation. The system becomes self-sustaining by capturing and recycling endogenous cytokines, eliminating the need for continuous exogenous IL-2 administration and its associated toxicities.

Inventive Principle:

Principle #25Self-service

2Productivity

If co-stimulatory signaling domains such as CD28 and 4-1BB are included in CAR receptors, then secondary proliferative signal is improved, but co-stimulatory activity remains insufficient in solid tumors with low tumor associated antigen levels

Engineering Contradiction:

Improveco-stimulatory activityVSAvoidantigen-dependency

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent separates the co-stimulatory function from the antigen recognition function. The IL-2/Fc complex provides a dedicated co-stimulatory signal independent of antigen binding, allowing T-cells to receive proliferation signals even when antigen levels are low, thereby improving reliability in solid tumor environments.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention merges the IL-2 receptor binding domain with the Fc region to create a bifunctional molecule that simultaneously provides antigen-independent co-stimulation and enhances CAR T-cell persistence. This combined structure delivers both co-stimulatory signaling and metabolic support to T-cells.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20250213708A1Chimeric transmembrane proteins and uses thereof

Publication Date: 2025.07.03 KITE PHARMA INC

AI summary

Provided herein are chimeric transmembrane proteins, nucleic acids encoding these chimeric transmembrane proteins, and mammalian cells containing these nucleic acids, and methods of making and using these mammalian cells.