In vitro and in vivo activity of sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (Trop-2) in uterine serous carcinoma

Han, Chanhee; Perrone, Emanuele; Zeybek, Burak; Bellone, Stefania; Tymon‐Rosario, Joan; Altwerger, Gary; Menderes, Gulden; Feinberg, Jacqueline; Haines, Kaitlin; Karger, Mariana Espinal Muller; Bianchi, Anna; Zammataro, Luca; Manzano, Aránzazu; Bonazzoli, Elena; Manara, Paola; Buza, Natália; Hui, Pei; Ratner, Elena; Silasi, Dan‐Arin; Huang, Gloria S.; Azodi, Masoud; Schwartz, Peter E.; Lopez, Salvatore; Santin, Alessandro D.

doi:10.1016/j.ygyno.2019.11.018

Cited by 19 publications

(9 citation statements)

References 27 publications

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“…6,45 These data are in line with earlier preclinical studies of uterine, ovarian, and endometrial adenocarcinoma models, all of which overexpress Trop-2, where SG demonstrated a significant in vitro cytotoxic effect on primary Trop-2-positive cell lines, a significant bystander killing effect in the tumor microenvironment, and antitumor effects in Trop-2-positive xenograft models. [46][47][48] A study of SG in endometrial carcinoma is underway in Trop-2-enriched patients to determine whether additional efficacy may be achieved by selecting patients with high Trop-2-expressing tumors (NCT04251416).…”

Section: Discussionmentioning

confidence: 99%

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial

et al. 2021

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Background: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. Patients and methods: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. Results: In the OSP (n ¼ 495, median age 61 years, 68% female; UGT1A1*28 homozygous, n ¼ 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n ¼ 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade !3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1*28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1*1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n ¼ 1/11; 9.1% ORR). Conclusions: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

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Section: Discussionmentioning

confidence: 99%

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial

et al. 2021

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“…AR47A6.4.2 and Pr1E11 have low internalization activity and high cell surface retention, with robust in vivo antibody-dependent cellular cytotoxicity (ADCC) and/or in pancreatic, colon, breast, and prostate cancer models or complement-dependent cytotoxicity (CDC) activity [ 32 , 33 ]. The Trop-2-targeting ADC drug sacituzumab govitecan that was developed by Immunomedics has shown excellent therapeutic efficacy in a Phase III clinical trial for the treatment of patients with metastatic triple-negative breast cancer (mTNBC) and has been approved by the Food and Drug Administration (FDA) in April 2020 [ 34 ]. Such antibody-based strategies benefit from the high specificity and affinity of monoclonal antibodies to target tumor cells, whereas they are often associated with some pharmaceutical, pharmacological, and pharmacokinetic issues such as poor penetration, blood retention, and significant immunogenicity compared with antibody fragments or small molecules [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Specific Nanobodies against Trop-2 for Tumor Targeting

Wang

Lin

et al. 2022

IJMS

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Trophoblast cell-surface antigen 2 (Trop-2) is a tumor-associated antigen that is connected with the development of various tumors and has been identified as a promising target for tumor immunotherapy. To date, the immunotherapy against Trop-2 mainly relies on the specific targeting by monoclonal antibody in antibody-drug conjugate (ADC). Alternatively, the single domain antibodies of nanobodies (Nbs) possesses unique properties such as smaller size, better tissue penetration, etc., to make them good candidates for tumor targeting. Thus, it was proposed to develop anti-Trop-2 Nbs for tumor targeting in this study. Generally, three consecutive rounds of bio-panning were performed against immobilized recombinant Trop-2, and yielded three Nbs (Nb60, Nb65, and Nb108). The affinity of selected Nbs was determined in the nanomolar range, especially the good properties of Nb60 were verified as a promising candidate for tumor labeling. The binding to native Trop-2 was confirmed by flow cytometry against tumor cells. The inhibitory effects of the selected Nbs on tumor cell proliferation and migration were confirmed by wound healing and Transwell assay. The clear localization of the selected Nbs on the surface of tumor cells verified the potent labeling efficiency. In conclusion, this study provided several Nbs with the potential to be developed as targeting moiety of drug conjugates.

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“…This indicated that sacituzumab might not block the formation of a TROP-2 cis - or trans -assembly, although the possibility of binding-induced stereo hindrance could not be excluded. Sacituzumab alone does not effectively suppress tumors in vivo , which also indicates that sacituzumab does not inhibit the function of TROP-2 during tumor metastasis ( Han et al., 2020 ). Therefore, the tumor suppressive effects of sacituzumab govitecan are mainly induced by SN-38 after binding to TROP-2 expressed in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Structural insights into the cis and trans assembly of human trophoblast cell surface antigen 2

et al. 2021

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Summary Human trophoblast cell surface antigen 2 (TROP-2) is an important target of tumor therapy, and antibody-drug conjugates with sacituzumab targeting TROP-2 have been approved for the treatment of triple-negative breast cancer. Here, we report the crystal structures of TROP-2-ECD, which can be either cis- or trans- dimers depending on which distinct but overlapping interfaces is used to engage with monomers. The cis- or trans -tetrameric forms of TROP-2 can also be assembled with a non-overlapping interface with either cis - or trans- dimerization, suggesting that cis - and trans- dimers cluster on the cell surface. The binding site of sacituzumab on TROP-2 is mapped to be located on a stretched polypeptide in CPD (Q237-Q252), which is not involved in either cis- or trans- interactions. The present findings will improve understanding of the molecular assembly of TROP-2 on tumor cells and shed light on future design of biologics for tumor therapy.

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In vitro and in vivo activity of sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (Trop-2) in uterine serous carcinoma

Cited by 19 publications

References 27 publications

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial

Identification and Characterization of Specific Nanobodies against Trop-2 for Tumor Targeting

Structural insights into the cis and trans assembly of human trophoblast cell surface antigen 2

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