Synthesis and Biological Evaluation of a Carbamate-Containing Tubulysin Antibody–Drug Conjugate
| Autor: | Kavitha Vemuri, Sanjeev Gangwar, Vangipuram S. Rangan, Mary Huber, Tom Kempe, Janette Sung, Colin Chong, Jennifer Juliano, Alice Stevens, Severino Cuison, Shrikant Deshpande, Meghan Greenbaum, Heng Cheng, Chetana Rao-Naik, Chin Pan, Qiang Cong, Jerry Jiang, Gregory D. Vite, Dan Dervin, David Passmore, Andrea L. Tatum, Eilene Kwok, Pina M. Cardarelli |
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| Rok vydání: | 2020 |
| Předmět: |
Antibody-drug conjugate
Immunoconjugates Lung Neoplasms Biomedical Engineering Pharmaceutical Science Antineoplastic Agents Bioengineering Mice SCID 02 engineering and technology GPI-Linked Proteins 01 natural sciences Mice chemistry.chemical_compound Animals Humans Cytotoxic T cell Ovarian Neoplasms Pharmacology Dipeptide biology 010405 organic chemistry Organic Chemistry 021001 nanoscience & nanotechnology In vitro 0104 chemical sciences body regions Biochemistry chemistry Mesothelin Cancer cell biology.protein Female Carbamates Antibody 0210 nano-technology Oligopeptides Linker Biotechnology Conjugate |
| Zdroj: | Bioconjugate Chemistry. 31:2350-2361 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/acs.bioconjchem.0c00429 |
| Popis: | Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic payloads directly into tumor cells via specifically binding to the target cell surface antigens. ADCs can enhance the anti-tumor effects of antibodies, and increase the delivery of cytotoxic payloads to cancer cells with a better therapeutic index. An ADC was prepared with a potent carbamate-containing tubulysin analogue attached to an anti-mesothelin antibody via a Cit-Val dipeptide linker. An aniline functionality in the tubulysin analogue was created to provide a site of linker attachment via an amide bond that would be stable in systemic circulation. Upon ADC internalization into antigen-positive cancer cells, the Cit-Val dipeptide linker was cleaved by lysosomal proteases, and the drug was released inside the tumor cells. The naturally occurring acetate of tubulysin was modified to a carbamate to reduce acetate hydrolysis of the ADC in circulation and to increase the hydrophilicity of the drug. The ADC bearing the monoclonal anti-mesothelin antibody and the carbamate-containing tubulysin was highly potent and immunologically specific to H226 human lung carcinoma cells in vitro, and efficacious at well-tolerated doses in a mesothelin-positive OVCAR3 ovarian cancer xenograft mouse model. |
| Databáze: | OpenAIRE |
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