Engineered TGF-beta Receptors for Cancer Treatment
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Solution Overview
Problem
Current treatments for inhibiting TGF-β signaling in the tumor microenvironment are ineffective and often have dose-limiting toxicity, necessitating the development of new modalities to modulate TGF-β activities.
Innovation Solution
The development of recombinant polypeptides comprising an extracellular domain and a transmembrane domain from TGF-β receptors, engineered to lack amino acid residues responsible for signaling and phosphorylation, which can be used to inhibit TGF-β activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule and antibody-based inhibitors of TGF-β binding and signaling are used, then TGF-β immunosuppressive effects are limited, but dose-limiting toxicity occurs
Solution Approach 1:
The patent extracts only the extracellular domain of the TGF-β receptor that is responsible for ligand binding, while removing the intracellular signaling domain. This creates a dominant-negative inhibitor that blocks TGF-β binding without activating downstream signaling pathways, thereby achieving immunosuppression inhibition without the toxicity associated with systemic TGF-β pathway inhibition
Solution Approach 2:
The invention modifies specific local properties of the TGF-β receptor by deleting amino acid residues in the intracellular domain that are responsible for signaling and phosphorylation (residues 185-205 in TGF-βRI). This localized modification allows the receptor to retain binding function while losing signaling capability, creating a precise tool for blocking immunosuppression without broad toxicity
2Reliability
If truncated TGF-βRII is used as dominant-negative inhibitor, then downstream signaling is prevented, but effective cancer treatment is not achieved
Solution Approach 1:
The patent optimizes the parameters of the dominant-negative TGF-β receptor by selecting specific extracellular domain configurations and transmembrane domain compositions that enhance cell surface expression and ligand binding affinity. These parameter optimizations ensure sufficient inhibition of TGF-β-mediated immunosuppression to achieve effective cancer treatment
Solution Approach 2:
The invention creates a composite receptor structure combining the extracellular domain of TGF-β receptor with a transmembrane domain from various sources (TGF-βRI, TGF-βRII, PDGFR, CD4, CD8, CD28, etc.). This composite structure achieves improved stability, expression levels, and dominant-negative activity compared to simple truncations
Data Source
AI summary
Provided herein are engineered receptors that include an extracellular domain (ECD) from a TGF-β receptor, a transmembrane domain (TMD), and that lack amino acid residues for signaling and phosphorylation, where such receptors are involved in cytokine signaling, for modulating TGF-β signaling, for methods of modulating TGF-β signaling, and for treating cancer using chimeric antigen receptors.