Catabolism of antibody drug conjugates and characterization methods
| Autor: | Stephen Bowlin, Jayaprakasam Bolleddula, Mohammad Shadid |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Immunoconjugates
medicine.drug_class Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Pharmacology Monoclonal antibody 030226 pharmacology & pharmacy Biochemistry Mass Spectrometry 03 medical and health sciences 0302 clinical medicine Pharmacokinetics In vivo Neoplasms Drug Discovery medicine Cytotoxic T cell Animals Humans Cytotoxicity Molecular Biology Chemistry Catabolism Organic Chemistry Antibodies Monoclonal Small molecule In vitro body regions 030220 oncology & carcinogenesis Molecular Medicine Chromatography Liquid |
| Zdroj: | Bioorganicmedicinal chemistry. 25(12) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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