CD28 Transmembrane Domain CAR for Tumor Potency
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) for immunotherapy face limitations in potency, particularly in solid tumors due to low target antigen density and immune suppressive factors, and often result in neurological toxicities from cytokine storms, with unclear effects of non-signaling modules like hinge and transmembrane domains on CAR proliferation and therapeutic efficacy.
Innovation Solution
Development of enhanced CAR constructs incorporating a hinge domain and a CD28 transmembrane domain, which promotes dimerization and reduces interactions with endogenous CD28, leading to improved CAR-T cell survival, reduced toxicity, and enhanced therapeutic efficacy by modulating T-cell activation and function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR constructs are used, then CAR-T cells can be generated for immunotherapy, but the potency is limited particularly in solid tumors due to low target antigen density and immune suppressive factors
Solution Approach 1:
The patent changes the structural parameters of the CAR by incorporating a CD28 transmembrane domain and a hinge domain capable of promoting dimerization. This structural modification alters the signaling properties of the CAR, enhancing its potency and ability to function in the immune suppressive microenvironment of solid tumors.
Solution Approach 2:
The patent creates a composite CAR structure by combining multiple functional domains: an antigen-binding moiety, a hinge domain from CD28 or IgG4, a CD28 transmembrane domain, and costimulatory signaling domains. This composite structure integrates multiple functions to overcome the limitations of conventional CARs in solid tumor therapy.
2Reliability
If CAR-T products are administered, then therapeutic effects are achieved, but neurological and other toxicities occur as a consequence of cytokine storm
Solution Approach 1:
The patent modifies the signaling parameters of CAR-T cells by using a CD28 transmembrane domain instead of conventional transmembrane domains. This change alters the activation threshold and signaling intensity, reducing excessive cytokine production while maintaining therapeutic efficacy.
Solution Approach 2:
The patent employs a hinge domain capable of promoting dimerization, which provides partial activation signaling through the CD28 transmembrane domain. This partial signaling mechanism prevents excessive activation and cytokine storm while still achieving sufficient therapeutic effect.
3Stability of the object's composition
If non-signaling modules like hinge and transmembrane domains are used in CAR constructs, then structural integrity is maintained, but their effects on CAR proliferation and therapeutic efficacy remain largely unclear
Solution Approach 1:
The patent systematically varies the parameters of non-signaling modules by testing different hinge domains (CD28 vs. IgG4) and the CD28 transmembrane domain to determine their optimal configuration for both structural integrity and therapeutic efficacy.
Solution Approach 2:
The CD28 transmembrane domain and hinge domain combination provides self-regulating properties, where the dimerization capability of the hinge domain automatically modulates the signaling strength based on CAR density and clustering, optimizing therapeutic efficacy without external intervention.
Data Source
AI summary
The present disclosure relates generally to the field of immuno-therapeutics, and particularly relates to novel chimeric polypeptides, e.g., chimeric antigen receptors (CARs) that include a transmembrane domain from CD28 and a hinge domain. In some cases, the hinge domain is capable of promoting dimerization of the CARs. The disclosure also provides compositions and methods useful for producing such molecules, as well as methods for the detection and treatment of health conditions, such as proliferative diseases (e.g., cancer).