Chimeric Proteins With Attenuated Receptor Binding
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Solution Overview
Problem
Current therapeutic use of cytokines, hormones, and growth factors is limited by systemic toxicity and off-target effects due to promiscuous binding, leading to undesirable side effects and reduced efficacy.
Innovation Solution
Development of chimeric proteins with modified soluble agents that have reduced affinity at therapeutic receptors, allowing for controlled, localized action through attachment of targeting moieties, thereby minimizing off-target effects and enhancing safety and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If soluble agents (cytokines, hormones, growth factors) are administered therapeutically, then therapeutic effects are achieved, but systemic toxicity and off-target effects occur due to promiscuous binding
Solution Approach 1:
The soluble agent is divided into two functional parts: a modified soluble agent with reduced promiscuous binding and a targeting moiety that provides specific localization. This segmentation allows the therapeutic effect to be concentrated at the target site while reducing systemic exposure and off-target effects.
Solution Approach 2:
The chimeric protein is designed to have different binding properties at different locations: the modified soluble agent portion provides reduced promiscuous binding throughout the body, while the targeting moiety provides high-affinity binding specifically at the target site, creating localized therapeutic action.
2Quantity of substance
If soluble agents are used at higher doses to overcome promiscuous binding, then therapeutic coverage is improved, but side effects increase
Solution Approach 1:
The targeting moiety acts as an intermediary that directs the modified soluble agent specifically to the target site. This mediator function ensures that the therapeutic agent reaches the intended location efficiently, allowing lower overall doses to achieve the same therapeutic coverage, thereby reducing side effects.
3Power
If the soluble agent maintains high affinity at the therapeutic receptor, then therapeutic activity is strong, but non-therapeutic signaling and sequestration occur at other receptors
Solution Approach 1:
The binding affinity parameters of the soluble agent are deliberately modified through mutations to create a differential affinity profile: reduced affinity at promiscuous receptors to prevent non-therapeutic signaling, while maintaining or restoring affinity at the therapeutic receptor through the targeting moiety to preserve therapeutic activity.
Data Source
AI summary
The present invention relates, in part, to targeted chimeric proteins with beneficial therapeutic effects, including, for example, effects mediated by mutant forms of soluble agents that are part of the chimeric proteins. Pharmaceutical compositions comprising the chimeric proteins are also provided. The present invention finds use in the treatment of various disease and disorders.