Type I–II Extracellular Domain Chimeras to Counter Immune Evasion
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Solution Overview
Problem
Existing immunotherapies for cancer and autoimmunity, such as checkpoint inhibition therapies, often fail to effectively enhance immune responses due to cancer cells evading immune detection and destruction through strategies like down-regulation of antigens and up-regulation of immune inhibitory molecules, leading to suppressed immune cell activity.
Innovation Solution
Development of chimeric proteins comprising extracellular domains of immune inhibitory and stimulatory signals, engineered to disrupt inhibitory signals and enhance stimulatory signals, such as PD-1 with OX40L, to coordinate positive and negative immune signals, thereby stimulating an effective immune response against tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint inhibition therapy is used to stimulate immune response, then immune activation is improved, but cancer cells evade immune detection through up-regulation of immune inhibitory molecules
Solution Approach 1:
The patent combines an immune inhibitory signal domain (e.g., PD-1 extracellular domain) and an immune stimulatory signal domain (e.g., OX40L extracellular domain) into a single chimeric protein. This merging allows the therapeutic agent to simultaneously deliver both inhibitory and stimulatory signals, coordinating positive and negative immune signals to overcome cancer immune evasion while maintaining immune activation effectiveness
Solution Approach 2:
The chimeric protein acts as an intermediary that delivers coordinated immune signals. The protein structure includes a linker connecting the inhibitory and stimulatory domains, allowing it to bind to both inhibitory receptors (like PD-L1) and stimulatory receptors (like OX40) on immune cells, thereby mediating a balanced immune response that overcomes evasion mechanisms
2Reliability
If multiple separate immunotherapies are used to address immune inhibition and stimulation, then immune response coordination is improved, but treatment complexity increases
Solution Approach 1:
The patent merges multiple functional domains (inhibitory signal and stimulatory signal) into a single chimeric protein molecule. This consolidation allows coordinated delivery of both immune inhibitory and stimulatory signals through one therapeutic agent, simplifying the treatment regimen while maintaining effective immune signal coordination
Solution Approach 2:
The chimeric protein is designed with multi-functionality, capable of interacting with both inhibitory and stimulatory immune receptors. This single molecule performs multiple functions that would otherwise require separate therapeutic agents, reducing treatment complexity while achieving coordinated immune response modulation
Data Source
AI summary
The present invention relates to, inter alia, compositions and methods, including chimeric proteins that find use in the treatment of disease, such as immunotherapies for cancer and autoimmunity. In part, the invention provides, in various embodiments, fusions of extracellular domains of transmembrane proteins that can have stimulatory or inhibitory effects.