FAP-Binding Chimeric Proteins for CAF Polarization in Tumors
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Solution Overview
Problem
There is a need for improved therapies targeting fibroblast activation protein (FAP) to treat diseases associated with aberrant fibroblasts, such as cancer and fibrotic diseases, as existing therapies are inadequate in modifying the tumor microenvironment and CAF functions.
Innovation Solution
Development of FAP binding agents, including chimeric proteins and Fc-based chimeric protein complexes, that target FAP to alter the disease microenvironment, recruit immune cells, and deliver therapeutic agents to sites of interest, such as tumors, while maintaining or modulating FAP signaling as needed.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If FAP binding agents are used to target and modify the tumor microenvironment, then the ability to treat cancer and fibrotic diseases is improved, but the complexity of the therapeutic approach increases
Solution Approach 1:
The FAP binding agent is designed as a modular chimeric protein complex consisting of distinct functional domains: an FAP binding domain for target recognition, an Fc domain for immune recruitment, and optional therapeutic payload domains. This segmentation allows each component to perform its specific function while simplifying the overall design and manufacturing process.
Solution Approach 2:
The FAP binding agent incorporates multiple functions within a single molecular construct: it binds to FAP for targeting, recruits immune cells through Fc receptor engagement, and delivers therapeutic payloads. This multi-functionality reduces the need for multiple separate therapeutic agents and simplifies the treatment regimen.
2Adaptability or versatility
If FAP binding agents are designed to recruit immune cells and deliver therapeutic agents, then the therapeutic capability is enhanced, but the manufacturing complexity increases
Solution Approach 1:
The Fc domain of the chimeric protein complex automatically mediates immune cell recruitment through natural Fc receptor binding, eliminating the need for additional engineering of recruitment mechanisms. The protein self-assembles into functional complexes with appropriate stoichiometry, reducing manufacturing complexity.
Solution Approach 2:
The therapeutic agent is constructed as a composite chimeric protein combining protein domains with defined sequences and structures. This composite approach allows modular assembly using established protein expression and purification technologies, simplifying manufacturing while enabling versatile therapeutic functions.
3Adaptability or versatility
If the FAP binding agent modulates FAP signaling, then the ability to polarize CAFs is improved, but the risk of off-target effects increases
Solution Approach 1:
The FAP binding agent exhibits high binding affinity and specificity for FAP, concentrating its modulatory effect locally at the tumor microenvironment where FAP is overexpressed. This localized action minimizes off-target effects on normal tissues with low or no FAP expression while maintaining effective CAF polarization.
Solution Approach 2:
The Fc domain acts as an intermediary that translates FAP binding into controlled immune recruitment and therapeutic delivery. This intermediary mechanism provides a buffer that reduces direct signaling effects, allowing for more controlled and predictable modulation of FAP signaling with fewer off-target effects.
Data Source
AI summary
The present invention relates, in part, to agents, chimeric proteins and protein complexes that bind fibroblast activation protein (FAP) and their use as diagnostic and therapeutic agents. The present invention further relates to pharmaceutical compositions comprising the FAP binding agents, chimeric proteins and protein complexes and their use in the treatment of various diseases.