Research Papers:
Trop2 is a novel target for solid cancer therapy with sacituzumab govitecan IMMU132 an antibodydrug conjugate ADC*
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David M. Goldenberg1, Thomas M. Cardillo1, Serengulam V. Govindan1, Edmund A. Rossi1, Robert M. Sharkey1
1Immunomedics, Inc., Morris Plains, NJ, USA
*Presented in part as a lecture by DMG, “Challenging the Dogmas: Clinical Efficacy of SN-38-conjugated Antibodies in Solid Tumors,” at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapy, Barcelona, Spain, November 20, 2014.
Correspondence to:
David M. Goldenberg, e-mail: [email protected]
Keywords: antibody-drug conjugate, Trop-2, SN-38, solid cancers, triple-negative breast cancer
Received: April 28, 2015 Accepted: June 05, 2015 Published: June 18, 2015
ABSTRACT
Trop-2 is a novel target for ADC therapy because of its high expression by many solid cancers. The rational development of IMMU-132 represents a paradigm shift as an ADC that binds a well-known moderately-cytotoxic drug, SN-38, to the anti-Trop-2 antibody. In vitro and in vivo studies show enhanced efficacy, while there is a gradual release of SN-38 that contributes to the overall effect. IMMU-132 is most efficacious at a high drug:antibody ratio (DAR) of 7.6:1, which does not affect binding and pharmacokinetics. It targets up to 136-fold more SN-38 to a human cancer xenograft than irinotecan, SN-38′s prodrug. IMMU-132 delivers SN-38 in its most active, non-glucuronidated form, which may explain the lower frequency of severe diarrhea than with irinotecan. Thus, this ADC, carrying a moderately-toxic drug targeting Trop-2 represents a novel cancer therapeutic that is showing promising activity in patients with several metastatic cancer types, including triple-negative breast cancer, non-small-cell and small-cell lung cancers.