Anti-Trop-2 Antibody-Drug Conjugates with Stable Linker
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Solution Overview
Problem
Current anti-Trop-2 antibody-drug conjugates (ADCs) comprising SN-38 face challenges in maintaining efficacy while minimizing adverse events due to undesired release of SN-38 from the conjugate, leading to instability and reduced therapeutic effectiveness.
Innovation Solution
Development of ADCs with a novel linker moiety that stabilizes the conjugation of SN-38 to an anti-Trop-2 antibody, allowing selective release at Trop-2-expressing cells, thereby enhancing stability and reducing adverse events.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If a pH-sensitive carbonate bond linker is used in ADC-CL2A-SN38, then SN-38 releases quickly in serum (half-life ~1 day), but this causes high frequency of adverse events
Solution Approach 1:
The patent changes the chemical parameters of the linker from a pH-sensitive carbonate bond to a stable carbamate bond, altering the release kinetics of SN-38. This parameter change extends the serum half-life from ~1 day to 87.5 days while reducing adverse events, achieving both controlled release and improved safety profile
2Stability of the object's composition
If a stable carbamate-containing linker (CL2E) is used, then serum half-life extends to 87.5 days, but in vivo efficacy is diminished
Solution Approach 1:
The patent introduces a dynamic element to the stable carbamate linker by incorporating a protease-cleavable peptide sequence (GGFG) that remains stable in circulation but can be dynamically activated by proteases at the tumor site. This dynamic characteristic allows the linker to maintain stability during transport (87.5 days half-life) while enabling effective drug release for in vivo efficacy
3Productivity
If SN-38 is conjugated to anti-Trop-2 antibody, then targeted delivery to cancer cells is achieved, but undesired release in serum causes toxicity
Solution Approach 1:
The patent uses the carbamate-containing linker with protease-cleavable peptide as an intermediary between the anti-Trop-2 antibody and SN-38. This intermediary protects SN-38 from premature release in serum while enabling controlled release at the target site through protease cleavage, thus maintaining targeted delivery efficiency while reducing systemic toxicity
Data Source
AI summary
This disclosure relates to antibody-drug conjugates (ADCs) comprising an anti-Trop-2 antibody. Provided herein are compositions comprising such ADCs, as well as methods of making and using the same.