Immunoreceptor Inhibitory Fusion Proteins for TNFα-TNFR Blocking
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Solution Overview
Problem
Current technologies lack effective methods to inhibit the binding of TNFα to TNFR1 and TNFR2, which can lead to uncontrolled immune responses and inflammation, and there is a need for specific proteins that can modulate these interactions to suppress or enhance immune responses as required.
Innovation Solution
Development of immunoreceptor inhibitory proteins that specifically bind to TNF superfamily members such as TNFα and LTα, inhibiting their binding to TNFR1 and TNFR2, and incorporating heterologous moieties like Ig Fc regions to enhance stability and functionality, with fusion proteins and conjugates designed to target these interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunoreceptor inhibitory proteins are designed to specifically bind TNFα and inhibit its binding to TNFR1 and TNFR2, then the ability to modulate immune responses is improved, but the complexity of protein design and manufacturing increases
Solution Approach 1:
The immunoreceptor inhibitory protein is designed with distinct functional domains: an N-terminal region for TNFα binding and a C-terminal Ig Fc region for stability and effector functions. This segmentation allows each domain to independently perform its specific function while simplifying the overall design process
Solution Approach 2:
The protein combines two different functional elements into a single fusion protein: the immunoreceptor inhibitory domain that binds TNFα and the Ig Fc domain that provides stability and mediates immune effector functions. This composite structure achieves multiple objectives simultaneously
2Duration of action of stationary object
If heterologous moieties like Ig Fc regions are incorporated to enhance stability and functionality, then the duration of action is improved, but the manufacturing complexity increases
Solution Approach 1:
The Ig Fc domain serves multiple functions simultaneously: it enhances protein stability, extends half-life through FcRn recycling, enables effector functions like ADC and CDC, and provides a standardized module that simplifies manufacturing by using well-characterized protein domains
Solution Approach 2:
Incorporating the Ig Fc domain changes the physicochemical parameters of the fusion protein, including increased stability, extended half-life, and modified immunogenicity profile, while leveraging existing manufacturing protocols for Ig-containing proteins
3Reliability
If fusion proteins and conjugates are designed to target TNFα-TNFR interactions, then the effectiveness of immune modulation is improved, but the device complexity increases
Solution Approach 1:
The immunoreceptor inhibitory protein acts as an intermediary molecule that binds to TNFα and prevents its interaction with TNFR1 and TNFR2, thereby mediating the suppression of pro-inflammatory responses without requiring direct modification of the receptor or ligand structures
Solution Approach 2:
The Ig Fc domain provides self-service functions by mediating effector mechanisms such as antibody-dependent cytotoxicity and complement-dependent cytotoxicity, enabling the fusion protein to exert immune modulatory effects through its own structure without requiring additional components
Data Source
AI summary
Provided herein are immunoreceptor inhibitory proteins and compositions (e.g., pharmaceutical compositions) comprising the same; as well as methods of making the immunoreceptor inhibitory proteins and compositions. The immunoreceptor inhibitory proteins provided herein are useful in pharmaceutical compositions and methods of use (including, e.g., inhibiting binding of one or more TNFRSF member to one or more TNFLSF member (e.g., binding of TNFα to TNFR1 and/or TNFR2; and/or binding of LTα to TNFR1 and/or TNFR2).