Antibody Chemically Induced Dimerizer for Selective Cellular Therapy Control
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Solution Overview
Problem
Current chemically induced dimerizer (CID) systems lack a general method for design and identification, and most are limited to natural proteins, leading to immunogenicity concerns and toxicity issues in human therapy, with a need for expanded development using human-derived proteins or antibodies.
Innovation Solution
Development of antibody chemically induced dimerizer (AbCID) systems comprising a first CID component interacting with a small molecule and a second CID component binding specifically to the complex, using human-derived binding moieties and adapter moieties to create a molecular switch for regulating cellular therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If natural proteins are used to develop CID systems, then the systems can be developed using known binding partners, but immunogenicity concerns and toxicity issues arise in human therapy
Solution Approach 1:
The patent changes the fundamental parameter of protein origin from natural/non-human to human-derived. By using human antibodies and human protein scaffolds instead of natural proteins like FKBP12 or FRB, the system maintains manufacturability while eliminating immunogenicity concerns in human therapy
Solution Approach 2:
The patent employs readily available human-derived components (human antibodies, human protein domains) that can be produced through standard biotechnological methods, replacing complex natural protein systems with more accessible, clinically-compatible alternatives
2Reliability
If conventional CID systems are used, then protein-protein interactions can be controlled, but selectivity for the small-molecule-bound form is limited
Solution Approach 1:
The patent uses phage display technology to pre-select and screen antibodies that specifically recognize the small-molecule-bound conformation of proteins. This preliminary selection process ensures high selectivity before the CID system is deployed for controlling protein-protein interactions
Solution Approach 2:
The patent replaces conventional chemical or physical methods of inducing dimerization with an antibody-based recognition system. The antibody's natural binding mechanism is harnessed to achieve conformation-specific recognition, providing superior selectivity compared to traditional CID approaches
3Object-affected harmful factors
If human-derived binding moieties are used in AbCID systems, then immunogenicity is reduced, but the system complexity increases compared to natural protein CIDs
Solution Approach 1:
The patent creates a universal platform using human-derived components that can be applied to multiple different protein targets and small molecules. The modular architecture with interchangeable human antibodies and protein scaffolds allows the system to address various therapeutic applications without increasing inherent complexity
Solution Approach 2:
The patent divides the CID system into distinct functional modules: a human-derived binding moiety that recognizes the small molecule, an adapter domain that enables dimerization, and a protein of interest. This segmentation allows each component to be optimized independently while maintaining overall system simplicity
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 AbCID systems provide improved selectivity and reduced immunogenicity, enabling precise control of protein-protein interactions and biological processes, with potential for safer and more effective therapeutic applications.
Implementation Method 1
a first binding moiety capable of interacting with a small molecule to form a complex between the first CID component and the small molecule
Implementation Method 2
a second binding moiety that specifically binds to the complex between the small molecule and the first binding moiety
Data Source
AI summary
Chemically induced dimerizers (AbCIDs) have emerged as one of the most powerful tools to artificially regulate signaling pathways in cells; however, no facile method to identify or design these systems currently exists. The present invention provides a methodology to rapidly generate antibody-based chemically induced dimerizers (AbCIDs) from known small-molecule-protein complexes by selecting for synthetic antibodies that recognize the chemical epitope created by the bound small molecule. Success of this strategy is demonstrated by generating ten chemically-inducible antibodies against the BCL-xL/ABT-737 complex. Three of the antibodies are highly selective for the BCL-xL/ABT-737 complex over BCL-xL alone. Two exemplary important cellular applications of AbCIDs are demonstrated by applying them intracellularly to induce CRISPRa-mediated gene expression and extracellularly to regulate CAR T-cell activation with the small molecule, ABT-737. ABT-737 is not toxic at the concentrations used to activate AbCIDs in cells. AbCIDs provided by this invention are new and orthogonal AbCIDs, expanding the limited toolbox of available CIDs.