Non-Dimerizing TGF-Beta Monomers for Receptor-Selective Signaling Blockade
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Solution Overview
Problem
Existing TGF-β signaling pathways contribute to the progression of fibrotic disorders and certain types of cancer by promoting extracellular matrix protein expression and suppressing immune surveillance, and current methods lack effective inhibitors to block these pathways.
Innovation Solution
Engineered TGF-β monomers with specific amino acid modifications, such as cysteine to serine substitution, deletion of residues 52-71, and additional charge-increasing substitutions, prevent dimerization and enhance affinity for the TβRII receptor, thereby inhibiting TGF-β signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If TGF-β dimerization is allowed to proceed naturally, then the TGF-β signaling pathway is activated which promotes extracellular matrix protein expression and immune suppression, but this leads to progression of fibrotic disorders and cancer
Solution Approach 1:
The patent segments the TGF-β dimer structure by introducing a cleavable peptide bond between the two TGF-β monomers. This allows the dimer to be divided into separate monomers under specific conditions, thereby controlling the activation of the TGF-β signaling pathway and preventing uncontrolled disease progression
Solution Approach 2:
The patent modifies the chemical parameters of the TGF-β dimer by incorporating a non-natural amino acid with a cleavable peptide bond. This parameter change enables conditional activation of the signaling pathway, allowing for controlled therapeutic effects while minimizing harmful outcomes
2Adaptability or versatility
If a TGF-β dimer with cleavable peptide bond is used, then controlled activation of TGF-β signaling is achieved, but the structural complexity of the protein increases
Solution Approach 1:
The patent extracts the essential functional element (the cleavable peptide bond) from a complex control system and incorporates it directly into the TGF-β dimer structure. This simplifies the overall system by eliminating the need for external activation mechanisms while maintaining controlled signaling capability
Solution Approach 2:
The TGF-β dimer is designed to be self-activating through the cleavable peptide bond that can be spontaneously hydrolyzed or cleaved by endogenous enzymes. This self-service mechanism eliminates the need for complex external activation systems, reducing overall structural complexity while maintaining adaptability
Data Source
AI summary
Recombinant transforming growth factor (TGF)-β monomers modified to inhibit dimerization and block TGF-β signaling are described. The recombinant TGF-β monomers lack the ability to bind and recruit TGF-β type I receptor (TβRI), but retain the capacity to bind the high affinity TGF-β type II receptor (TβRII), and in some instances, include mutations that increase their affinity for TβRII. Nucleic acid molecules and vectors encoding the recombinant TGF-β monomers are also described. Isolated cells, such as T cells, can be re-programmed with a TGF-β monomer-encoding nucleic acid or vector to secrete the monomer. Use of the recombinant TGF-β monomers and/or cells producing the recombinant TGF-β monomers, to inhibit TGF-β signaling, such as to treat disorders associated with aberrant TGF-β signaling, are also described.