Chimeric Antigen Receptors Targeting Fibronectin for Solid Tumors

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Solution Overview

Problem

Current CAR-T cell therapies have limited efficacy against solid tumors due to challenges such as lack of tumor-specific antigens, therapeutic resistance, tumor heterogeneity, and immunosuppressive tumor microenvironments, particularly in prostate, breast, and lung cancers.

Innovation Solution

Development of chimeric antigen receptors (CARs) targeting onco-fetal variants of fibronectin expressed in the extracellular matrix of solid tumors, specifically designed to bind the IIICS or EDB domains of fibronectin, combined with nucleic acids and vectors for modifying immune cells to enhance tumor targeting and immune response.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CAR-T cell therapies are used, then hematologic malignancies can be treated effectively, but solid tumors remain resistant due to lack of tumor-specific antigens and immunosuppressive microenvironment

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidapplicability to solid tumors

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the target antigen parameter from conventional tumor-specific antigens (like CD19) to oncofetal fibronectin, which is overexpressed in solid tumors. This parameter change enables CAR-T cells to effectively target solid tumors while maintaining efficacy against hematologic malignancies

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent segments the fibronectin protein into specific domains (EDB, EDA, IIICS) and targets these specific segments with CAR-T cells. This segmentation allows precise targeting of oncofetal fibronectin variants expressed in solid tumors while avoiding normal fibronectin in healthy tissues

Inventive Principle:

Principle #1Segmentation

2Ease of operation

If CAR-T cells are designed to target solid tumors, then tumor infiltration is needed, but dense immunosuppressive microenvironment prevents T cell infiltration

Engineering Contradiction:

ImproveT cell infiltration capabilityVSAvoidimmunosuppressive tumor microenvironment

Core Design Contradiction:

Ease of operationVSObject-affected harmful factors

Solution Approach 1:

The patent uses oncofetal fibronectin as an intermediary target that is abundantly present in the extracellular matrix of solid tumors. This intermediary provides a accessible target for CAR-T cells to bind and infiltrate through the dense tumor microenvironment, overcoming physical barriers

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If conventional antigens are targeted, then specific cancer types can be treated, but tumor heterogeneity and therapeutic resistance develop

Engineering Contradiction:

Improvetherapeutic responseVSAvoidresistance to therapeutic failure

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent targets oncofetal fibronectin, which is universally expressed across multiple solid tumor types including prostate, breast, colorectal, and lung cancers. This universal target provides broad applicability and reduces tumor heterogeneity-related resistance, making the therapy versatile across different cancer types

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20220380447A1Fibronectin targeting chimeric antigen receptors (CARS)

Publication Date: 2022.12.01 THE TRUSTEES OF THE UNIV OF PENNSYLVANIA

AI summary

The present disclosure provides compositions and methods comprising chimeric antigen receptors (CARs) capable of binding tumor-specific isoforms of fibronectin.