Dual Binding Agents Enable Lysosomal Surface Protein Degradation
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Solution Overview
Problem
Existing protein degrader technologies, such as AbTACS, achieve only approximately 60% degradation of target proteins and are limited to intracellular mechanisms, making them less effective for degrading cell surface proteins.
Innovation Solution
Development of dual binding agents with IgG scaffolds that specifically bind to both a membrane-associated E3 ligase and a target surface protein, enhancing degradation efficiency by ubiquitination and internalization through the lysosomal pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AbTACs utilize a standard IgG bisspecific antibody format to bring a cell surface E3 ligase into proximity of a membrane protein of interest, then the degradation mechanism is established through the lysosomal pathway, but the degradation efficiency is limited to approximately 60% of target protein
Solution Approach 1:
The patent modifies the IgG scaffold parameters by fusing binding domains to specific chains (heavy or light chain C-terminus) rather than using traditional bispecific antibody formats. This structural parameter change enables increased degradation efficiency (Dmax) while maintaining the lysosomal degradation pathway reliability
Solution Approach 2:
The patent creates a composite structure by combining an IgG scaffold with additional binding domains fused to the heavy or light chains. This composite approach allows simultaneous binding to both the E3 ligase and target protein, achieving enhanced degradation efficiency beyond the 60% limit of conventional AbTACs
2Reliability
If degrader technologies utilize intracellular mechanisms of action, then the mechanism is well-established, but the targeting is limited to proteins with cytoplasmic domains and cannot effectively degrade cell surface proteins
Solution Approach 1:
The patent uses the IgG scaffold as an intermediary structure that bridges the extracellular space and intracellular degradation machinery. By fusing binding domains to the IgG chains, it creates a mediator that can simultaneously engage cell surface proteins and E3 ligases, enabling degradation of membrane-associated proteins that were previously inaccessible to intracellular mechanisms
Solution Approach 2:
The patent creates a universal degradation platform that can target both cytoplasmic and cell surface proteins. The IgG scaffold with fused binding domains serves multiple functions: binding to E3 ligases, binding to target proteins with extracellular domains, and directing both types of proteins to the lysosomal degradation pathway
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 dual binding agents achieve increased degradation efficiency, with a maximum degradation (Dmax) of at least 20% of target proteins, effectively reducing target cell proliferation and providing therapeutic benefits for neoplastic diseases.
Implementation Method 1
binds to both a membrane-associated ubiquitin E3 ligase and a target surface protein... such that the target surface protein is ubiquitinated and degraded as a result of binding
Implementation Method 2
targeted protein degradation is a promising new therapeutic strategy... utilize event-driven pharmacology... durably abrogate all protein functions at once... trafficking to the lysosome for degradation
Data Source
AI summary
The present disclosure relates to, among other things, methods for degrading targeted surface proteins using the ubiquitin pathway by using a dual binding agent that binds the targeted surface protein and a membrane-associated ubiquitin E3 ligase. The disclosure also provides compositions and methods useful for producing such dual binding agents, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating an activity of a cell and/or for the treatment of various diseases such as cancers.