Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer

Abstract

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IMMU-140, a Novel SN-38 Antibody–Drug Conjugate Targeting HLA-DR, Mediates Dual Cytotoxic Effects in Hematologic Cancers and Malignant Melanoma

“…In particular, the same conjugation method has been used to create an anti-Trop-2 SN-38-ADC (sacituzumab govitecan, IMMU-132) that targets Trop-2 on solid tumors, and likewise has been shown to be superior to parental antibody both in vitro and in vivo (18,19,31). Further, it has demonstrated efficacy in heavily pretreated metastatic triple-negative breast cancer, as well as small-cell and non-small-cell lung cancer patients (14)(15)(16), suggesting that IMMU-140 may prove to be superior to its parental antibody clinically.…”

“…The moderately stable linker in these unconventional ADCs enables the drug to be released in the acidic pH of tumor microenvironment, while internalization further increases the drug's bioavailability. These design features, while not amenable to showing specificity in vitro, have resulted in encouraging clinical activity of other ADCs (anti-Trop-2 ADC, anti-CEACAM5 ADC) in solid cancer therapies (14)(15)(16)(17)30). In particular, the same conjugation method has been used to create an anti-Trop-2 SN-38-ADC (sacituzumab govitecan, IMMU-132) that targets Trop-2 on solid tumors, and likewise has been shown to be superior to parental antibody both in vitro and in vivo (18,19,31).…”

“…In an effort to improve the antitumor activity of IMMU-114, an ADC (IMMU-140) was developed by conjugating IMMU-114 with the active metabolite of irinotecan, SN-38. Other ADCs utilizing SN-38 (sacituzumab govitecan and labetuzumab govitecan) being studied in solid tumors have been well tolerated, having clinically significant objective responses in patients given multiple cycles over >6 months, and with manageable neutropenia being the major toxicity (13)(14)(15)(16)(17). Cytotoxicity mediated by SN-38 is through DNA breakage triggering the intrinsic apoptotic pathway, resulting in activation of the caspase cascade, PARP cleavage, and further DNA degradation (18)(19)(20).…”

The Application of Non-Invasive Apoptosis Detection Sensor (IADS) on Histone Deacetylation Inhibitors (HDACi) Induced Breast Cancer Cell Death

“…TNBC represents only 15-20% of patients with breast cancer. TNBC poor prognosis may be due to its unique histological features such as high grade, high proliferative rate, low apoptotic cells [9].…”

“…More recently, three clinical trials reported in the American Society of Clinical Oncology (ASCO) meeting of 2016 using new targeted therapies have presented the successful results of against triple negative breast cancer. These studies target to Trop2 [9], frizzled receptor and PD-L1 [10,11] oncoproteins in combination with the chemotherapy paclitaxel exhibit great potential to extend the lives of TNBC patients whose cancers have progressed after previous treatments. However, intense research is still carrying on to identify specific biomarkers and develop additional and effective treatment options.…”