Surrogate Cytokine Polypeptides for Receptor Dimerization
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Solution Overview
Problem
Current cytokine engineering approaches are limited in accessing the full scope of cytokine receptor signaling plasticity, particularly for cytokines that signal through Type I single-pass transmembrane receptors, which are not amenable to high-throughput medicinal chemistry approaches.
Innovation Solution
Development of engineered polypeptides as surrogate cytokine agonists, including single-chain and two-chain bispecific ligands that can dimerize cytokine receptors, such as IL-2, IL-10, and Type I IFN receptors, to modulate signaling pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If traditional cytokine engineering approaches are used, then existing cytokine ligands can be modified through affinity maturation and half-life extension, but the full scope of cytokine receptor signaling plasticity cannot be accessed
Solution Approach 1:
The invention segments the cytokine receptor binding interface by using separate antibody fragments (scFvs or VHHs) that can be independently designed and combined to target different receptor subunits, enabling systematic exploration of signaling plasticity without redesigning the entire cytokine molecule
Solution Approach 2:
The patent creates a universal platform where the same antibody fragment-based approach can be applied to multiple cytokine receptor systems (IL-2, IL-10, Type I IFN), allowing cross-application of binding modules to access signaling plasticity across different cytokine families
2Productivity
If medicinal chemistry library approaches are used, then biased agonists can be identified, but cytokine receptor systems are not amenable to these approaches due to large protein-protein contact surfaces
Solution Approach 1:
The invention extracts the cytokine ligand function and replaces it with antibody fragments that bind to receptor extracellular domains, separating the binding function from the traditional cytokine structure and enabling library-based screening of binding specificities
Solution Approach 2:
The patent introduces antibody fragments as intermediary molecules that bridge the gap between small molecule library screening and cytokine receptor systems, allowing high-throughput identification of biased agonists through fragment-based high-throughput screening
3Adaptability or versatility
If cytokine agonist therapeutics are limited to variations of the natural cytokine, then structural simplicity is maintained, but cytokine receptor signaling plasticity is not fully exploited
Solution Approach 1:
The invention introduces dynamic control of signaling plasticity by allowing selective combination of different antibody fragments with varying binding geometries and affinities, enabling tunable signaling outcomes that can be adjusted based on therapeutic needs
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The engineered polypeptides effectively induce downstream signaling activities, including phosphorylation of STAT proteins, and demonstrate potential in inhibiting viral replication, such as SARS-CoV-2, without inducing pro-inflammatory cytokine expression.
Implementation Method 1
Cytokines function to bind to receptor extracellular domains and dimerize them. The cytokine forms large protein-protein contact surfaces with the receptor ECDs to supply the binding energy needed to bridge two receptor subunits.
Implementation Method 2
The engineered polypeptides are capable of inducing dimerization of the indicated cytokine receptors. The ligands are single chain bispecific ligands that can include one or more antibody domains and can be mixed and matched to create libraries of dimerizing ligands.
Implementation Method 3
The engineered polypeptides effectively induce downstream signaling activities, including phosphorylation of STAT proteins
Data Source
AI summary
The present disclosure relates to to compositions and methods relating to cytokine agonists and their engineered polypeptides. The engineered polypeptides have specificity to receptors in immune systems including IL-2/15, Type I IFN and IL-10. The present disclosure also relates to methods for identifying surrogate cytokine agonists and to a system for engineering ligands that can compel formation of non-naturally-occurring cytokine receptor heterodimers. The present disclosure also relates to methods and system for identifying surrogate agonists for cell surface receptors including dimeric and trimeric receptors.