Targeted Mutant IFN-γ Chimeric Proteins for Lower Toxicity
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Solution Overview
Problem
Recombinant human interferon-gamma (IFN-γ) therapies suffer from short plasma half-life and significant side effects such as fever, chills, sweating, headache, myalgia, and cardiotoxicity, necessitating improved compositions with reduced toxicity and side effects.
Innovation Solution
Development of chimeric proteins with modified IFN-γ that have reduced affinity and/or biological activity for the IFN-γ receptor, combined with targeting moieties to recruit immune cells to specific sites, minimizing off-target effects and enhancing therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant human wild type IFN-γ is used as a therapeutic agent, then antiviral and immunomodulatory activities are achieved, but significant side effects including fever, chills, sweating, headache, myalgia, and cardiotoxicity occur
Solution Approach 1:
The patent applies local quality by creating chimeric proteins with modified IFN-γ that have reduced affinity for the IFN-γ receptor in non-target tissues, thereby localizing the therapeutic effect to specific sites while minimizing systemic side effects. The targeting moieties direct the protein to specific locations, creating a localized therapeutic action that spares non-target organs from toxicity.
Solution Approach 2:
The patent changes the binding affinity parameter of IFN-γ by introducing mutations that reduce its affinity for the IFN-γ receptor. This parameter modification allows the protein to maintain therapeutic activity at target sites while reducing off-target binding that causes side effects such as fever, chills, and cardiotoxicity.
2Reliability
If recombinant human IFN-γ is administered, then therapeutic activity is achieved, but frequent injections are required due to short plasma half-life
Solution Approach 1:
The patent creates composite chimeric proteins that combine modified IFN-γ with targeting moieties. This composite structure not only provides therapeutic activity but also extends plasma half-life through Fc region extensions or other modifying elements that enhance pharmacokinetic properties, reducing the frequency of administration.
3Power
If IFN-γ binds to the IFN-γ receptor with high affinity, then biological activity is maximized, but off-target effects and systemic toxicity increase
Solution Approach 1:
The chimeric protein with reduced affinity for IFN-γ receptor combines targeting moieties that locally concentrate the protein at specific sites. This creates a local quality distinction where high concentration occurs only at the target site, maximizing biological activity there while minimizing off-target effects systemically.
Solution Approach 2:
The targeting moiety acts as an intermediary that directs the modified IFN-γ to specific cells or tissues. This intermediary function allows the protein to achieve high local concentration at the target while avoiding non-specific binding to other tissues, thereby reducing off-target effects.
Data Source
AI summary
The present invention relates, in part, to chimeric proteins comprising a modified human IFN-γ having one or more mutations that confer reduced affinity and/or biological activity that is restorable by attachment to one or more targeting moieties. The one or more targeting moieties may have recognition domains which specifically bind to antigens or receptors of a tumor or an immune cell. The one or more recognition domains may be a single-domain antibody or a single-chain antibody (scFv). The application also provides use of the chimeric proteins as therapeutic agents.