Mutant CD28 Domain Enhances CAR-T Persistence

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Solution Overview

Problem

Current adoptive cell transfer therapies using T-cells with Chimeric Antigen Receptors (CARs) for cancer treatment face challenges in maintaining effective tumor targeting and immune cell persistence, with limitations in reducing tumor load and promoting sustained immune responses.

Innovation Solution

Engineering immune effector cells, such as T cells and NK cells, to express a CAR polypeptide with a mutant CD28 costimulatory domain that includes specific amino acid sequences for enhanced antigen binding and signaling, reducing Grb2 binding and promoting prolonged immune activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CAR therapy is used, then tumor targeting is achieved, but immune cell persistence and tumor load reduction are limited

Engineering Contradiction:

Improvetumor targeting effectivenessVSAvoidimmune cell persistence

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies the CD28 costimulatory domain by changing specific amino acid parameters (Y71 to F or W, N74 to A, V76 to I or L) to alter the molecular characteristics of the CAR. These parameter changes in the costimulatory domain enhance Grb2 binding affinity, which in turn improves immune cell persistence and tumor load reduction while maintaining the original tumor targeting capability.

Inventive Principle:

Principle #35Parameter changes

2Quantity of substance

If CAR therapy is used, then antigen binding is achieved, but sustained immune response is insufficient

Engineering Contradiction:

Improveantigen binding capacityVSAvoidsustained immune response

Core Design Contradiction:

Quantity of substanceVSDuration of action of stationary object

Solution Approach 1:

The patent creates a composite costimulatory domain structure that combines elements from CD28 with optimized amino acid sequences. This composite structure integrates the antigen recognition function with enhanced Grb2 binding capability, resulting in both maintained antigen binding capacity and improved sustained immune response duration.

Inventive Principle:

Principle #40Composite materials

3Ease of manufacture

If wild-type CD28 domain is used, then basic costimulation is provided, but Grb2 binding is reduced limiting therapeutic efficacy

Engineering Contradiction:

ImproveCAR construction simplicityVSAvoidtherapeutic efficacy

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent applies local quality modification by making specific amino acid changes only in the critical regions of the CD28 costimulatory domain (positions 71, 74, and 76) while leaving the rest of the sequence intact. This localized modification approach maintains the overall simplicity of CAR construction while significantly improving Grb2 binding and therapeutic efficacy.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20230312677A1CD28 compositions and methods for chimeric antigen receptor therapy

Publication Date: 2023.10.05 NOVARTIS AG

AI summary

The invention provides compositions and methods for treating diseases associated with expression of a cancer associated antigen as described herein. The invention also relates to chimeric antigen receptor (CAR) specific to a cancer associated antigen as described herein, vectors encoding the same, and recombinant T cells comprising the CARs of the present invention. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises an antigen binding domain that binds to a cancer associated antigen as described herein. The CAR may comprise a mutant CD28 costimulatory domain.