Humanized CD47-CAR-T Cells Targeting Tumor Antigen
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Solution Overview
Problem
Current adoptive T cell immunotherapy for cancer lacks improved efficacy and increased toxicity, particularly in targeting CD47-positive tumor cells which are often overexpressed in various cancers, leading to poor clinical outcomes.
Innovation Solution
Development of humanized CD47-CAR-T cells that specifically target CD47 tumor antigen using a chimeric antigen receptor (CAR) fusion protein comprising a single-chain variable fragment (scFv), a transmembrane domain, a co-stimulatory domain, and an activating domain, designed to selectively kill CD47-positive cancer cells while minimizing immune response and toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T cells are used to target tumor cells, then antitumor activity is improved, but toxicity increases
Solution Approach 1:
The patent applies parameter changes by modifying the CAR structure to include specific co-stimulatory domains (CD28, 4-1BB, OX40) and regulatory elements that alter the activation threshold and cytokine profile of CAR-T cells. This results in enhanced antitumor activity with reduced toxicities compared to conventional CAR-T cells
Solution Approach 2:
The patent creates composite CAR structures by combining multiple functional domains including scFv for antigen recognition, transmembrane domains for positioning, and multiple co-stimulatory domains (CD28, 4-1BB, OX40) within a single CAR construct. This composite structure enables simultaneous enhancement of persistence, proliferation, and reduced toxicity
2Duration of action of stationary object
If CAR-T cells with multiple co-stimulatory domains are used, then persistence and proliferation are improved, but device complexity increases
Solution Approach 1:
The patent merges multiple co-stimulatory domains (CD28, 4-1BB, OX40) into single CAR constructs, combining the beneficial effects of different co-stimulatory signals into one integrated receptor structure. This approach improves persistence and proliferation while managing structural complexity through rational domain selection and arrangement
3Measurement precision
If CD47-targeting CAR-T cells are developed, then specificity against tumor cells is improved, but manufacturing complexity increases
Solution Approach 1:
The patent uses single-chain variable fragments (scFv) derived from existing anti-CD47 antibodies as the antigen-recognition domain in the CAR construct. This copying approach allows rapid development of CD47-specific CAR-T cells with high targeting specificity while simplifying manufacturing compared to developing entirely new antigen-binding domains
Data Source
AI summary
The present invention provides a chimeric antigen receptor (CAR) fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) comprising VH and VL, wherein scFv has an activity against CD47, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. In one embodiment, the scFv is derived from a humanized anti-CD47 antibody. The present invention also provides T cells modified to express the CAR of the present invention.