B7-H3 CARs with 4-1BBL for Solid Tumor Therapy
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Solution Overview
Problem
Current CAR T cell-based therapies targeting solid tumors have limited success due to the dependency on specific molecular designs and the need for therapies that can recognize multiple solid tumors with minimal expression in normal tissues, as seen with B7-H3, which is a promising but underdeveloped target.
Innovation Solution
Development of chimeric antigen receptors (CARs) specifically binding to B7-H3, expressed with a 4-1BB ligand (4-1BBL), comprising an extracellular target-binding domain, a transmembrane domain, and a cytoplasmic signaling domain, enhanced by the inclusion of a 4-1BBL to improve effector function and antitumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If second generation (2G) CAR T cells are used to target solid tumors, then the therapy can recognize tumor antigens, but the antitumor activity is limited
Solution Approach 1:
The patent combines multiple functional domains into a single CAR molecule: the B7-H3 binding domain (for antigen recognition), the 4-1BB costimulatory domain (for T cell activation and persistence), and the CD3ζ signaling domain (for signal transduction). This merging of multiple functions into one integrated receptor overcomes the limited antitumor activity of 2G CARs by providing both antigen recognition and potent costimulatory signals simultaneously.
Solution Approach 2:
The CAR molecule is constructed as a composite of different functional protein domains: the extracellular B7-H3 binding domain, the transmembrane domain, the 4-1BB costimulatory domain, and the CD3ζ signaling domain. This composite structure integrates the beneficial properties of each domain to create a CAR with enhanced antitumor activity compared to simpler 2G designs.
2Adaptability or versatility
If CAR T cells are designed to target multiple solid tumors, then the therapy becomes more versatile, but the molecular design complexity increases
Solution Approach 1:
The patent creates a universal CAR platform targeting B7-H3, which is expressed across multiple solid tumor types including ovarian, pancreatic, lung, and breast cancers. By focusing on B7-H3 as a pan-solid tumor antigen, the same CAR molecular design can be applied universally across different cancer types, achieving versatility without requiring multiple different CAR designs for each tumor type.
Data Source
AI summary
The present invention provides a chimeric antigen receptor (CAR) comprising an extracellular target-binding domain comprising a B7-H3 binding moiety. The present invention further provides polynucleotides and recombinant vectors encoding such CARs. The present invention further provides isolated host cells and methods for preparing isolated host cells expressing the CARs. The present invention further provides pharmaceutical compositions comprising the isolated host cells and methods for treating a tumor using the pharmaceutical compositions.