Antibody Conjugates of 7-Ethyl-10-hydroxycamptothecin (SN-38) for Targeted Cancer Chemotherapy

• Published in: Journal of medicinal chemistry Vol. 51; no. 21; pp. 6916 - 6926
• Main Authors: Moon, Sung-Ju, Govindan, Serengulam V, Cardillo, Thomas M, D’Souza, Christopher A, Hansen, Hans J, Goldenberg, David M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.11.2008; Amer Chemical Soc
• Subjects: Acetylene - chemistry; Antibodies - chemistry; Antibodies - immunology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - immunology; Antineoplastic Agents - pharmacology; Azides - chemistry; Biological and medical sciences; Camptothecin - analogs & derivatives; Camptothecin - chemical synthesis; Camptothecin - chemistry; Camptothecin - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; General aspects; Humans; Kinetics; Life Sciences & Biomedicine; Medical sciences; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; ANTICANCER ACTIVITY; IRINOTECAN CPT-11; THERAPY; EFFICACY; METABOLISM; CAMPTOTHECIN; LINKERS; PRODRUGS; DERIVATIVES; PROSPECTS; Antineoplastic agent; Camptothecin derivatives; Stability; Enzyme; DNA topoisomerase; Enzyme inhibitor; Cytotoxicity; Monoclonal antibody; Immunoconjugate; Malignant tumor; In vitro; Biological activity; Irinotecan; Alkaloid; Chemotherapy; Isomerases; Treatment; Cell line; Active ingredient; Colon; Chemical synthesis; Tumor cell; Release; Cancer
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800719t

CPT-11 is a clinically used cancer drug, and it is a prodrug of the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin). To bypass the need for the in vivo conversion of CPT-11 and increase the therapeutic index, bifunctional derivatives of SN-38 were prepared for use in antibody-based targeted therapy of cancer. The general synthetic scheme incorporated an acetylene-azide click cycloaddition step in the design, a short polyethylene glycol spacer for aqueous solubility, and a maleimide group for conjugation. Conjugates of a humanized anti-CEACAM5 monoclonal antibody, hMN-14, prepared using these SN-38 derivatives were evaluated in vitro for stability in buffer and human serum and for antigen-binding and cytotoxicity in a human colon adenocarcinoma cell line. Conjugates of hMN-14 and SN-38 derivatives 16 and 17 were found promising for further development.