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Review
. 2019 Aug/Sep;11(6):987-995.
doi: 10.1080/19420862.2019.1632115. Epub 2019 Jul 18.

Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan

David M Goldenberg  1 , Robert M Sharkey  1
Affiliations
Review

Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan

David M Goldenberg et al. MAbs. 2019 Aug/Sep.

Abstract

Antibody-drug conjugates (ADCs) that exploit the active metabolite SN-38, which is derived from the popular anticancer drug, irinotecan (a camptothecin that inhibits the nuclear topoisomerase I enzyme, inducing double-stranded DNA breaks during the mitotic S-phase of affected cells), represent a substantial advance in the ADC field. SN-38 has been conjugated to a humanized antibody against trophoblast cell surface antigen 2 (TROP-2), which is involved in cancer signaling pathways and has increased expression by many cancer cell types, yielding the ADC sacituzumab govitecan. By conjugating a higher number of SN-38 molecules to the immunoglobulin (drug-to-antibody ratio = 7-8:1), and giving higher (10 mg/kg) and repeated therapy cycles (Days 1 and 8 of 21-day cycles), enhanced drug uptake by the targeted cancer cells is achieved. Based on a unique conjugation method, the lactone ring of the SN-38 molecule is stabilized and the molecule is protected from glucuronidation, a process that contributes to the untoward late diarrhea experienced with irinotecan. Finally, while the ADC is internalized, the use of a moderately stable linker permits release of SN-38 in an acidic environment of the tumor cell and its microenvironment, contributing to a bystander effect on neighboring cancer cells. Here, we discuss the development of sacituzumab govitecan and clinical results obtained using it for the management of patients with advanced, refractive breast, lung, and urinary bladder cancers. Sacituzumab govitecan, which is undergoing accelerated approval review by the US Food and Drug Administration while also being studied in Phase 3 clinical studies, was granted Breakthrough Therapy status from the FDA for advanced, refractory, metastatic triple-negative breast cancer patients.

Keywords: Antibody-drug conjugate; IMMU-132; SN-38; TROP-2; sacituzumab govitecan.

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Figures

Figure 1.
Figure 1.
Relative range of potency for some of the more commonly used ADC payloads against human cancer cell line in vitro (adapted from Nakada et al.60).
Figure 2.
Figure 2.
Sacituzumab govitecan (IMMU-132) composition. Sacituzumab govitecan is composed of the humanized monoclonal IgG (designated hRS7) that binds to TROP-2. The IgG is mildly reduced to expose 8 sulfhydryl-binding sites that are subsequently coupled to the CL2A-SN-38 linker-drug through the maleimide moiety of the CL2 linker. As indicated, the CL2A linker has a short PEG (polyethylene glycol) residue to aid in solubility and is coupled to SN-38 at the 20th position of the lactone ring, which stabilizes the ring from opening to the less active carboxylate form. The bond between CL2A and SN-38 is pH sensitive, being more susceptible to release in a low pH environment (e.g., found in lysosome or even in the microenvironment of tumors). The 10th position of SN-38 is protected from glucuronidation while SN-38 is bound to the IgG. Thus, SN-38, while bound to the antibody, remains in its most potent form until released.
Figure 3.
Figure 3.
(a) Waterfall plot illustrating the best response data in 108 triple-negative breast cancer patients treated with sacituzumab govitecan (adapted from Bardia et al.,50 with permission). (b–d) Tumor shrinkage by CT in triple-negative breast cancer patient given sacituzumab govitecan (from Bardia et al.38 with permission). Case study: A 48-year-old woman with an initial diagnosis of triple-negative breast cancer in received four prior lines of treatment (including an anti-PD-L1 immune checkpoint inhibitor) and presented with lung and lymph node metastases at enrollment. She achieved a partial response that started 1.7 months after initiation of treatment with sacituzumab govitecan, with the best response of 54% reduction at 9.0 months and progression occurring at 14.4 months (partial response duration, 12.7 months). (b) Baseline image of two of the three target lesions: a 24 x 19-mm left-upper-lung mass (arrow) and a mediastinal lymph node (17 x 29-mm; circle). (c) After 16 doses, these two target lesions decreased to 13 × 7 and 9 × 19 mm, respectively. (d) TROP-2 expression in an archived tumor specimen by immunohistochemistry that shows 1+ to 2+ staining (overall, 2+).
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This work was supported by the National Cancer Institute [CA39841].