Lipocalin-Fold Protein Interaction System for Tumor Therapy
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Solution Overview
Problem
Current chemically induced dimerization systems for protein-protein interactions are limited in their ability to regulate multiple processes simultaneously in vivo due to immunogenicity concerns and the use of xenogeneic proteins, and they often induce undesired heterodimerization, posing challenges for clinical applications, especially in tumor therapy.
Innovation Solution
Development of a ligand regulated protein-protein interaction system based on a lipocalin-fold molecule with a low molecular weight ligand, where the lipocalin-fold molecule binds to the ligand with an affinity at least 10-fold higher when bound, and the binding interaction partner is engineered to specifically recognize the ligand-bound state, reducing cross-reactivity and enhancing specificity for clinical use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If xenogeneic proteins are used in chemically induced dimerization systems, then dimerization function is achieved, but immunogenicity increases and reliability for clinical use decreases
Solution Approach 1:
The patent changes the protein origin parameter from xenogeneic to human proteins, specifically using the human FKBP12 and FRB domains. This parameter change eliminates immunogenicity issues while maintaining the chemically induced dimerization function, thereby resolving the contradiction between reliability for clinical use and harmful immunogenic effects.
Solution Approach 2:
The patent uses human protein domains (FKBP12 and FRB) that naturally exist in the human genome, copying endogenous protein functions to achieve dimerization. This approach avoids introducing foreign proteins that would trigger immune responses, thus improving clinical suitability while reducing immunogenicity.
2Adaptability or versatility
If existing CID systems are used, then dimerization is achieved, but simultaneous control of multiple processes is not possible
Solution Approach 1:
The patent creates a universal dimerization system using human FKBP12 and FRB domains that can simultaneously control multiple biological processes. The system's versatility is achieved through the ability to regulate different protein-protein interactions using the same chemical ligand (rapalogues), enabling multi-process control without requiring separate systems for each function.
Solution Approach 2:
The patent merges the regulation of multiple processes into a single integrated system. By using the same human protein domains and chemical ligands for different dimerization events, the system combines what would otherwise require separate control mechanisms into one unified platform, thereby achieving simultaneous control of multiple processes.
3Reliability
If FKBP-based homodimerization system is used, then apoptosis induction in T cells is achieved, but undesired heterodimerization occurs
Solution Approach 1:
The patent addresses the heterodimerization issue by using the natural heterodimerization capability of FKBP12 and FRB domains as a beneficial feature. Instead of viewing heterodimerization as a harmful side effect to be eliminated, the system exploits this property to achieve specific and reliable dimerization between different protein partners, thereby converting a potential harm into a useful function for controlled protein interaction.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The system allows for specific and robust regulation of protein-protein interactions in vivo, minimizing adverse reactions and enabling simultaneous control of multiple processes, thus being suitable for human pharmaceutical therapy, particularly in tumor treatment.
Implementation Method 1
the lipocalin-fold molecule can bind to the lipocalin-fold ligand; and wherein the lipocalin-fold molecule bound to the lipocalin-fold ligand binds to the lipocalin-fold binding interaction partner with an affinity which is at least 10-fold higher
Implementation Method 2
the lipocalin-fold molecule has at least a first conformation when the lipocalin-fold ligand is not bound to the lipocalin-fold molecule and at least a second conformation when the lipocalin-fold ligand is bound to the lipocalin-fold molecule
Implementation Method 3
Many are physical contacts with molecular associations between chains that occur in a cell or in a living organism in a specific biomolecular context. PPIs have also been used in the prior art for establishing screening systems or defined switches for pharmaceutical purposes
Data Source
AI summary
A ligand regulated protein-protein interaction system based on a lipocalin-fold molecule including: (a) a lipocalin-fold molecule; (b) a lipocalin-fold ligand with a low molecular weight of 1500 Da or below; and (c) a lipocalin-fold binding interaction partner, wherein the lipocalin-fold molecule can bind to the lipocalin-fold ligand; and wherein the lipocalin-fold molecule bound to the lipocalin-fold ligand binds to the lipocalin-fold binding interaction partner with an affinity which is at least 10-fold higher than the affinity of the lipocalin-fold molecule not bound to the lipocalin-fold ligand; and wherein the lipocalin-fold binding interaction partner is not a naturally occurring protein which has an affinity of <10 μM to any naturally occurring lipocalin-fold molecule in the presence of any lipocalin-fold ligand.