Catabolism of antibody drug conjugates and characterization methods
Mohammad Shadid1, Stephen Bowlin2, Jayaprakasam Bolleddula1
1Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, United States.
Abstract:
Antibody drug conjugates (ADCs) are large molecule therapeutics in which a cytotoxic payload is conjugated to a monoclonal antibody (mAb) via a linker. The molecules are designed to selectively bind to target-expressing cells, thus delivering therapeutic agents directly to the tumor. Chemical and enzymatic stability prior to reaching the target is an important factor for ADCs since it impacts their safety, efficacy, and pharmacokinetics (PK). One of the main reasons for off-target effects of ADCs is premature release of cytotoxic agents, either in the blood stream or at non-specific sites. Once an ADC is internalized by target-expressing cells, the cytotoxic payload and/or related catabolites are released through chemical or enzymatic cleavage within the cells. In some cases, the released payload and/or catabolites are effluxed into the systemic circulation and follow a small molecule disposition path. Since doses of ADCs are low, the concentration of cytotoxic payload and related catabolites/metabolites range from ng to μg levels in systemic circulation or tumors in clinical studies. Hence, it is challenging to identify these species without prior knowledge of the pathways of catabolism. The current review summarizes the mechanism of cleavage/catabolism of various types of linkers and available in vitro, in vivo, and bioanalytical methods for evaluation of catabolism of ADCs.
Insights
Antibody drug conjugates (ADCs) stability is crucial for safety and efficacy. This review details ADC linker cleavage mechanisms and methods to evaluate their catabolism, addressing challenges in detecting low-level cytotoxic payloads.
Area of Science:
- Pharmacology
- Biochemistry
- Drug Development
Background:
- Antibody drug conjugates (ADCs) are targeted therapeutics combining monoclonal antibodies (mAbs) with cytotoxic payloads.
- ADC stability is critical for preventing premature payload release and ensuring targeted delivery.
- Off-target effects and complex disposition pathways necessitate understanding ADC catabolism.
Purpose of the Study:
- To review ADC linker cleavage mechanisms.
- To summarize in vitro, in vivo, and bioanalytical methods for evaluating ADC catabolism.
- To address challenges in identifying low-concentration cytotoxic species.
Main Methods:
- Literature review of ADC linker chemistry and catabolism.
- Analysis of in vitro and in vivo studies on ADC stability.
- Overview of bioanalytical techniques for payload and metabolite detection.
Main Results:
- Various linker types exhibit distinct chemical and enzymatic cleavage mechanisms.
- Premature payload release is a key factor in ADC safety and efficacy.
- Detecting low-level circulating cytotoxic species requires sophisticated bioanalytical approaches.
Conclusions:
- Understanding ADC catabolism is essential for optimizing ADC design and therapeutic outcomes.
- Standardized methods are needed for robust evaluation of ADC stability and metabolite profiling.
- Further research into linker technology and bioanalysis will enhance ADC safety and efficacy.
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