Bispecific Binding Agent for Extracellular Protein Degradation
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Solution Overview
Problem
Current targeted protein degradation technologies are limited in their ability to degrade extracellular and cell surface proteins due to their intracellular mechanism of action, with most degraders only targeting intracellular proteins, and there is a need for a more efficient method to utilize endogenous internalization pathways for therapeutic purposes.
Innovation Solution
Development of fully recombinant bispecific binding agents that utilize LDL receptor-mediated internalization to target extracellular or cell surface proteins for lysosomal degradation, specifically binding to LDL receptors and target proteins, enabling efficient internalization and degradation of therapeutically relevant proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If heterobifunctional small molecules are used for targeted protein degradation, then intracellular proteins can be degraded effectively, but extracellular and cell surface proteins cannot be degraded due to intracellular mechanism of action limitation
Solution Approach 1:
The patent uses cell surface receptors (such as LDLR, ASGPR, M6PR) as intermediary mediators to bridge the gap between extracellular degrader molecules and intracellular degradation machinery. The receptors facilitate the internalization of the degrader-target complex, enabling extracellular proteins to be degraded through the cell's endogenous lysosomal pathway without requiring the degrader to penetrate the cell membrane directly.
Solution Approach 2:
The patent replaces the mechanical/proteasomal degradation system (used by traditional PROTACs) with a lysosomal degradation system. By redirecting the degradation pathway from the proteasome to the lysosome through receptor-mediated endocytosis, the system can process both intracellular and extracellular proteins effectively.
2Adaptability or versatility
If only a handful of receptors are used for targeted degradation, then the mechanism is simple, but the range of targetable proteins is limited
Solution Approach 1:
The patent identifies and utilizes multiple different cell surface receptors (LDLR, ASGPR, M6PR, LRP1, etc.) that can all serve the universal function of mediating degrader internalization. Each receptor can be paired with different targeting moieties to create specialized degraders for specific protein targets, allowing the same general mechanism to be applied across a broad range of therapeutic indications including cancer, metabolic diseases, and neurodegenerative disorders.
3Productivity
If LDL receptor-mediated internalization is used, then rapid internalization and lysosomal degradation is achieved, but the mechanism requires novel bispecific binding agents
Solution Approach 1:
The patent segments the degrader molecule into distinct functional domains: a targeting domain that binds to the specific protein target, a linker region that provides structural flexibility and optimal spacing, and a receptor-binding domain that mediates cell surface receptor engagement. This segmentation allows each component to be optimized independently while maintaining overall functionality.
Solution Approach 2:
The patent creates composite degrader molecules by combining different binding domains (such as antibody fragments, affinites, or peptides) with receptor-targeting moieties. These composite structures integrate the specificities of different binding components to achieve both high target affinity and efficient receptor-mediated internalization, resulting in enhanced degradation productivity.
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
This approach allows for the efficient degradation of a wide range of proteins, including membrane-associated and soluble targets, offering a promising therapeutic modality for various disorders such as cancer and metabolic diseases by leveraging the natural internalization pathways of LDL receptors.
Implementation Method 1
the binding of the first binding domain to the at least one endogenous LDL receptor results in the internalization of the target protein bound to the bispecific binding agent
Implementation Method 2
exploring a novel mechanism of action for targeting these receptors—i.e. co-opting their endogenous internalization to induce lysosomal degradation of a target protein
Data Source
AI summary
The present disclosure relates to targeted degradation platform technology. For example, the present disclosure relates to bispecific binding agents for degrading endogenous proteins, whether membrane-associated or soluble, using the lysosome pathway. The disclosure also provides methods useful for producing such 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 disorders.