BRM/BRG1-Targeting Antibody-Drug Conjugates for Targeted Degradation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing therapeutic approaches for targeting SMARCA2 and/or SMARCA4 in cancers with mutations, such as lung, melanoma, and pancreatic cancer, suffer from low efficacy and unwanted toxicities, necessitating more specific compounds that inhibit or degrade these proteins.
Innovation Solution
Development of antibody-drug conjugates comprising an antibody that targets specific antigens and a degrader compound linked via a linker to a small molecule E3 Ubiquitin Ligase binding moiety, which induces degradation of SMARCA2 and/or SMARCA4.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapeutic compounds are used to inhibit or degrade SMARCA2 and/or SMARCA4, then cancer cell proliferation is suppressed, but unwanted toxicities occur
Solution Approach 1:
The therapeutic compound is segmented into three distinct functional modules: (1) an antibody component that specifically binds to tumor-associated antigens, (2) a linker component that connects the antibody to the degrader, and (3) a degrader component (PROTAC molecule) that induces degradation of SMARCA2/4. This segmentation allows the toxic effects to be confined to the target tissue while the antibody provides specificity, thereby reducing systemic toxicities while maintaining therapeutic efficacy.
2Reliability
If small molecule-based approaches are used to target SMARCA2, then some inhibition is achieved, but efficacy is limited and toxicities increase
Solution Approach 1:
The antibody serves as an intermediary that delivers the degrader component specifically to tumor cells expressing the target antigen. This intermediary approach allows the degrader to reach its intracellular target (SMARCA2/4) with high precision, avoiding exposure of healthy tissues to the toxic degrader molecule, thereby improving the therapeutic index.
3Adaptability or versatility
If broad-spectrum inhibitors are used to target SWI/SNF complexes, then multiple cancer types may be affected, but specificity is reduced leading to increased toxicities
Solution Approach 1:
The antibody component provides local quality control by confining the degrader's action to specific tumor cells that express the target antigen. The degrader itself has broad potential activity against SWI/SNF complexes, but the antibody ensures this activity is only expressed locally at the tumor site, thereby maintaining versatility against different cancer types while minimizing systemic toxicities.
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 antibody-drug conjugates effectively target and degrade SMARCA2 and/or SMARCA4, providing a therapeutic benefit with reduced toxicities and improved efficacy in treating cancers with SMARCA4 mutations.
Implementation Method 1
a degrader compound linked via a linker to a small molecule E3 Ubiquitin Ligase binding moiety, which induces degradation of SMARCA2 and/or SMARCA4
Data Source
AI summary
The present disclosure provides antibody drug conjugates and drug-linker compounds comprising one or more degrader compounds which comprise a target protein binding moiety and an E3 ubiquitin ligase binding moiety that binds a Von Hippel-Lindau E3 Ubiquitin Ligase or a Cereblon E3 Ubiquitin Ligase, and methods of use thereof.