Chimeric MyD88 Receptors Enhance Solid Tumor CAR-T Efficacy

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Solution Overview

Problem

Current CAR T cell therapies have limited success against solid tumors and other diseases due to inadequate costimulatory strategies beyond CD28 or 4-1BB.

Innovation Solution

Development of chimeric MyD88 receptors with specific extracellular, transmembrane, and cytoplasmic domains, including target-binding moieties like anti-IL-13 scFv and PD1, to provide enhanced costimulation for improved immunotherapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional costimulatory domains (CD28 or 4-1BB) are used in CAR T cell therapy, then the therapy structure is simple and easy to manufacture, but the efficacy against solid tumors is limited

Engineering Contradiction:

Improveefficacy against solid tumorsVSAvoidreceptor structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent combines the MyD88 signaling domain with traditional CAR structure to create a chimeric receptor that integrates both antigen recognition and alternative costimulation functions into a single molecular entity, thereby improving efficacy while maintaining structural integration

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The chimeric MyD88 receptor functions as a composite molecular structure combining extracellular target-binding domains, transmembrane domains, and intracellular MyD88 signaling domains, creating a multifunctional receptor that addresses limitations of conventional single-domain costimulatory approaches

Inventive Principle:

Principle #40Composite materials

2Reliability

If additional costimulatory strategies are explored beyond CD28 or 4-1BB, then the immunotherapy efficacy may be improved, but the device complexity and manufacturing difficulty increase

Engineering Contradiction:

Improveimmunotherapy efficacyVSAvoidmanufacturing ease

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The MyD88-based chimeric receptor serves multiple functions including antigen recognition, signal transduction, and costimulation within a single molecular construct, reducing the need for multiple separate components and simplifying manufacturing processes while maintaining enhanced therapeutic efficacy

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If chimeric MyD88 receptors with multiple domains are developed, then T cell activation and anti-tumor activity are enhanced, but the receptor structure becomes more complex

Engineering Contradiction:

ImproveT cell activation and anti-tumor activityVSAvoidreceptor structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The chimeric MyD88 receptor is segmented into distinct functional modules including extracellular target-binding moieties, transmembrane anchoring domains, and intracellular MyD88 signaling domains, allowing each segment to perform its specific function while contributing to overall enhanced T cell activation and anti-tumor activity

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20230340040A1Chimeric myd88 receptors

Publication Date: 2023.10.26 ST JUDE CHILDRENS RES HOSPITAL INC

AI summary

The present disclosure provides chimeric MyD88 receptors. Also provided are polynucleotides encoding the chimeric MyD88 receptors, vectors comprising the polynucleotides encoding the chimeric MyD88 receptors, and cell compositions comprising the chimeric MyD88 receptors, polynucleotides and/or vectors. Pharmaceutical compositions comprising the polypeptides, polynucleotides, vectors, or cells of the present disclosure, and their uses in treating a disease in a subject are also provided.