Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC)*

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.

Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

“…IMMU-132 was found to deliver much higher levels of SN-38 to tumors than irinotecan and, importantly, all of the SN-38 delivered to the tumor by IMMU-132 is released in its most potent form. In relationship to gastrointestinal toxicity, the much lower amounts of SN-38G in the serum and significantly lower amounts of SN-38/SN38G in the intestine with IMMU-132 are expected to reduce the risk for severe diarrhea in patients, which is confirmed in clinical studies (34)(35)(36)(37)(38). Thus, IMMU-132 is an ADC that appears to have unique properties that combine to make an effective therapeutic agent in the solid cancers tested.…”

Liposomal curcumin and its application in cancer

“…Even so, 5-year survival rate is only 16%, though new drugs of anti-lung cancer such as angiogenesis-targeted drugs, epidermal growth factor receptor (EGFR)-targeted drugs, protein peptides of anti-lung cancer and lung cancer antibody drugs were developed. [97][98][99][100][101][102] Recently, a study reported that nanoliposomes using sodium hyaluronate and trimethyl CS form polymer-glycerosomes that can effectively deliver CUR to lung so as to improve the therapeutic index of CUR. 103 Recently, many studies reported that CUR liposomes have anticancer activity.…”

RN927C, a Site-Specific Trop-2 Antibody–Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models

“…The association of Trop-2 expression with advanced disease and/or clinical outcome in multiple tumor types, and the relatively restricted expression in normal adult tissues, underscores the potential benefit of targeting Trop-2 to fill an unmet need in cancer treatment. An anti-Trop-2 SN38 conjugate, hRS7-CL2A-SN-38 (IMMU-132), consisting of a humanized Trop-2 antibody conjugated to SN38, the active component of irinotecan, has been shown to be efficacious in several epithelial cancer cell line xenograft models (20)(21)(22). IMMU-132 (sacituzumab govitecan) is currently being tested in clinical trials for solid tumors and has reported encouraging therapeutic activity in patients with difficult-to-treat cancers (23).…”