Anti-Sp17 monoclonal antibody-doxorubicin conjugates as molecularly targeted chemotherapy for ovarian carcinoma.
Sperm protein 17 (Sp17) is selectively overexpressed in several human malignancies including ovarian carcinoma, but is absent or expressed at low levels in most normal tissues. Previous work from our group characterized an anti-Sp17 monoclonal antibody (clone 3C12) and showed that it specifically targeted tumor cells. In this report, we investigated whether a novel immunoconjugate containing 3C12 linked to the chemotherapeutic agent doxorubicin [(DOX) Adriamycin] had antitumor activity against ovarian cancer cell lines and tumor models. DOX was conjugated to 3C12 using a linker, and the specificity of 3C12-DOX was examined in Sp17-positive SKOV3 and Sp17-negative COC2 ovarian cancer cells using cell-based ELISA and internalization assays. The cytotoxicity of 3C12-DOX was assessed with the MTT assay, and its therapeutic effectiveness was evaluated in immunodeficient mice bearing SKOV3 cells. In vitro, the 3C12-DOX immunoconjugate specifically bound to and was internalized by Sp17-positive SKOV3 cells but did not bind to Sp17-negative cells. Treatment with 3C12-DOX (0.001 to 10 μg/mL) decreased the viability of SKOV3 cells in a Sp17-specific manner. In vivo, 3C12-DOX (3 mg/kg) induced the regression of established SKOV3 xenograft tumors in BALB/c mice compared with control treatment. The antitumor effects of 3C12-DOX were significantly associated with the induction of apoptosis in tumor cells. In addition, 3C12-DOX showed no observable adverse effects or toxicity when compared with DOX alone in mice bearing ovarian tumor xenografts. Our findings suggest that 3C12-DOX may be a potential antibody-drug conjugate for clinical development.
Laboratory of Molecular Biology, Institute of Medical Laboratory Sciences, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210002, People's Republic of China, strive1225@126.com.
Jia-Xi
JX
Song
Fang-Qiu
FQ
Li
Wang-Li
WL
Cao
Xuan
X
Jia
Li-Ning
LN
Shi
Jing-Fen
JF
Lu
Chun-Fang
CF
Ma
Qian-Qian
QQ
Kong
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000954:Antigens, Surface / Q000276:immunology*; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins / Q000276:immunology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D018796:Immunoconjugates; D008565:Membrane Proteins; C090172:SPA17 protein, human; D004317:Doxorubicin