Precursor Proteins for Targeted Cytokine Activation
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Solution Overview
Problem
Current cytokine-based cancer therapies face challenges in achieving effective concentrations in tumor tissue, leading to systemic distribution and adverse effects due to the need for large cytokine quantities, and issues with antigen specificity, resulting in off-target toxicity.
Innovation Solution
A set of precursor proteins, each comprising two polypeptides associated via dimerization domains, where at least one moiety is functionally inactive, undergoes polypeptide chain exchange to form a functionally active receptor ligand or enzyme, allowing targeted activation at the tumor site with reduced off-target toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If large quantities of cytokines are administered to achieve effective concentrations in tumor tissue, then therapeutic efficacy is improved, but systemic adverse effects worsen
Solution Approach 1:
The cytokine is divided into two separate precursor proteins that cannot exert biological activity individually. These precursors are administered systemically without adverse effects, and only activate at the tumor site through polypeptide chain exchange, achieving localized high concentration without systemic toxicity
Solution Approach 2:
The inactivation moiety acts as an intermediary that temporarily blocks cytokine activity during systemic circulation. At the tumor site, the inactivation moiety is removed through polypeptide chain exchange with the activation moiety, releasing the active cytokine locally without systemic exposure
2Object-affected harmful factors
If cytokines are fused to tumor-targeting antibodies to reduce systemic distribution, then off-target toxicity is reduced, but antigen specificity challenges persist
Solution Approach 1:
The targeting function and cytokine function are segmented into separate precursor proteins. Both precursors can bind to the target antigen, ensuring that cytokine activation occurs only at cells expressing the target antigen, thereby improving specificity compared to antibody-cytokine fusions
Solution Approach 2:
The invention changes the activation parameter from dependence on antibody-cytokine fusion stability to dependence on polypeptide chain exchange between two precursors. This exchange only occurs at the target site where both precursors are bound, providing more reliable antigen-specific activation
3Reliability
If precursor proteins are designed to undergo polypeptide chain exchange to form active cytokine, then targeted activation is improved, but device complexity increases
Solution Approach 1:
The single active cytokine is segmented into two inactive precursor proteins with complementary dimerization domains. This segmentation enables targeted activation through spontaneous polypeptide chain exchange at the tumor site, achieving high reliability without requiring complex external activation mechanisms
Solution Approach 2:
The precursor proteins are designed to automatically undergo polypeptide chain exchange when both are bound to the target antigen, without requiring external enzymes or complex activation systems. The system self-activates through the inherent instability of the heterodimeric interface, simplifying the overall mechanism
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
This approach enables targeted activation of therapeutically desired functional moieties at the tumor site, reducing systemic toxicity and improving the efficacy of cytokine-based cancer therapies by ensuring precise delivery and action.
Implementation Method 1
upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed
Implementation Method 2
each precursor protein comprises two polypeptides that are associated with each other via dimerization domains
Data Source
AI summary
The present invention relates to a set of precursor proteins comprising an inactivated receptor ligand or enzyme and methods for their use in therapy.