Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody–Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers
Top Cited Papers
- 8 May 2015
- journal article
- research article
- Published by American Chemical Society (ACS) in Bioconjugate Chemistry
- Vol. 26 (5), 919-931
- https://doi.org/10.1021/acs.bioconjchem.5b00223
Abstract
Sacituzumab govitecan (IMMU-132) is an antibody–drug conjugate (ADC) made from a humanized anti-Trop-2 monoclonal antibody (hRS7) conjugated with the active metabolite of irinotecan, SN-38. In addition to its further characterization, as the clinical utility of IMMU-132 expands to an ever-widening range of Trop-2-expressing solid tumor types, its efficacy in new disease models needs to be explored in a nonclinical setting. Unlike most ADCs that use ultratoxic drugs and stable linkers, IMMU-132 uses a moderately toxic drug with a moderately stable carbonate bond between SN-38 and the linker. Flow cytometry and immunohistochemistry disclosed that Trop-2 is expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast (TNBC), colonic, prostate, and lung. While cell-binding experiments reveal no significant differences between IMMU-132 and parental hRS7 antibody, surface plasmon resonance analysis using a Trop-2 CM5 chip shows a significant binding advantage for IMMU-132 over hRS7. The conjugate retained binding to the neonatal receptor, but it lost greater than 60% of the antibody-dependent cell-mediated cytotoxicity activity compared to that of hRS7. Exposure of tumor cells to either free SN-38 or IMMU-132 demonstrated the same signaling pathways, with pJNK1/2 and p21WAF1/Cip1 upregulation followed by cleavage of caspases 9, 7, and 3, ultimately leading to poly-ADP-ribose polymerase cleavage and double-stranded DNA breaks. Pharmacokinetics of the intact ADC in mice reveals a mean residence time (MRT) of 15.4 h, while the carrier hRS7 antibody cleared at a similar rate as that of the unconjugated antibody (MRT ∼ 300 h). IMMU-132 treatment of mice bearing human gastric cancer xenografts (17.5 mg/kg; twice weekly × 4 weeks) resulted in significant antitumor effects compared to that of mice treated with a nonspecific control. Clinically relevant dosing schemes of IMMU-132 administered either every other week, weekly, or twice weekly in mice bearing human pancreatic or gastric cancer xenografts demonstrate similar, significant antitumor effects in both models. Current Phase I/II clinical trials (ClinicalTrials.gov, NCT01631552) confirm anticancer activity of IMMU-132 in cancers expressing Trop-2, including gastric and pancreatic cancer patients.This publication has 49 references indexed in Scilit:
- Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signalingGenes & Development, 2012
- Cervical carcinomas overexpress human trophoblast cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized monoclonal anti-Trop-2 antibodyAmerican Journal of Obstetrics and Gynecology, 2011
- Trop-2 Overexpression in Poorly Differentiated Endometrial Endometrioid Carcinoma: Implications for Immunotherapy With hRS7, a Humanized Anti–Trop-2 Monoclonal AntibodyInternational Journal of Gynecologic Cancer, 2011
- High-grade, chemotherapy-resistant primary ovarian carcinoma cell lines overexpress human trophoblast cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized monoclonal anti-Trop-2 antibodyGynecologic Oncology, 2011
- Uterine serous papillary carcinomas overexpress human trophoblast-cell-surface marker (trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-trop-2 monoclonal antibodyCancer, 2011
- γH2AX and cancerNature Reviews Cancer, 2008
- Antibody Conjugates of 7-Ethyl-10-hydroxycamptothecin (SN-38) for Targeted Cancer ChemotherapyJournal of Medicinal Chemistry, 2008
- High expression of TROP2 correlates with poor prognosis in pancreatic cancerBritish Journal of Cancer, 2008
- Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cellsBritish Journal of Cancer, 2008
- Motifs for molecular recognition exploiting hydrophobic enclosure in protein–ligand bindingProceedings of the National Academy of Sciences of the United States of America, 2007