Sacituzumab govitecan in triple-negative breast cancer

Nonneville, Alexandre de; Gonçalves, Anthony; Mamessier, Émilie; Bertucci, François

doi:10.21037/atm-22-813

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…Sacituzumab govitecan-hziy (Trodelvy ® ) against TROP2, approved for solid cancers such as breast cancer in 2020, was internalized via RME. The payload SN-38 was released by double ester hydrolysis of the CL2A linker at low pH within lysosomes [ 30 , 31 , 32 ]. It was revealed that SN-38 crossed the plasma apical membrane via carrier-mediated transport using transporters different from organic anion-transporting polypeptides (OATP) and the monocarboxylate transporter (MCT) in Caco-2 cells [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

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Delivery of Drugs into Cancer Cells Using Antibody–Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect

Tashima

2022

Antibodies

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Innumerable people worldwide die of cancer every year, although pharmaceutical therapy has actualized many benefits in human health. For background, anti-cancer drug development is difficult due to the multifactorial pathogenesis and complicated pathology of cancers. Cancer cells excrete hydrophobic low-molecular anti-cancer drugs by overexpressed efflux transporters such as multiple drug resistance 1 (MDR1) at the apical membrane. Mutation-driven drug resistance is also developed in cancer. Moreover, the poor distribution of drug to cancer cells is a serious problem, because patients suffer from off-target side effects. Thus, highly selective and effective drug delivery into solid cancer cells across the membrane should be established. It is known that substances (10–100 nm in diameter) such as monoclonal antibodies (mAbs) (approximately 14.2 nm in diameter) or nanoparticles spontaneously gather in solid tumor stroma or parenchyma through the capillary endothelial fenestration, ranging from 200–2000 nm, in neovasculatures due to the enhanced permeability and retention (EPR) effect. Furthermore, cancer antigens, such as HER2, Nectin-4, or TROP2, highly selectively expressed on the surface of cancer cells act as a receptor for receptor-mediated endocytosis (RME) using mAbs against such antigens. Thus, antibody–drug conjugates (ADCs) are promising anti-cancer pharmaceutical agents that fulfill accurate distribution due to the EPR effect and due to antibody–antigen binding and membrane permeability owing to RME. In this review, I introduce the implementation and possibility of highly selective anti-cancer drug delivery into solid cancer cells based on the EPR effect and RME using anti-cancer antigens ADCs with payloads through suitable linkers.

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Section: Discussionmentioning

confidence: 99%

“…(b) PEGs are used to enlarge the protein size and to improve water solubility. In fact, sacituzumab govitecan-hziy (Trodelvy ® ) has PEG 8 in the linker [ 30 , 31 , 32 ]. However, the degree of PEGylation is thought to be restricted due to the size of an IgG molecule, because excess PEGs might counteract the nature of mAbs.…”

Section: Discussionmentioning

confidence: 99%

Delivery of Drugs into Cancer Cells Using Antibody–Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect

Tashima

2022

Antibodies

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“…Currently, three ADCs are approved in BC [ 3 ]. Trastuzumab emtansine in the HER2+ subtype [ 4 ], trastuzumab deruxtecan in the HER2+ [ 5 ] and HER2-low [ 6 ] subtypes, and sacituzumab govitecan in the triple-negative subtype (TN) [ 7 ] and recently the HR+/HER2- subtype [ 8 ]. Many others are under development, including our anti-nectin-4 ADC [ 9 , 10 ] and the ladiratuzumab vedotin anti-LIV1 ADC (SGN-LIV1A, Seagen; [ 11 , 12 ]).…”

Section: Introductionmentioning

confidence: 99%

Prognostic and Predictive Value of LIV1 Expression in Early Breast Cancer and by Molecular Subtype

et al. 2023

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Background: LIV1 is a transmembrane protein that may become a new therapeutic target through the development of antibody–drug conjugates (ADCs). Few studies are available regarding the assessment of LIV1 expression in clinical breast cancer (BC) samples. Methods: We analyzed LIV1 mRNA expression in 8982 primary BC. We searched for correlations between LIV1 expression and clinicopathological data, including disease-free survival (DFS), overall survival (OS), pathological complete response to chemotherapy (pCR), and potential vulnerability and actionability to anti-cancer drugs used or under development in BC. Analyses were performed in the whole population and each molecular subtype separately. Results: LIV1 expression was associated with good-prognosis features and with longer DFS and OS in multivariate analysis. However, patients with high LIV1 expression displayed a lower pCR rate than patients with low expression after anthracycline-based neoadjuvant chemotherapy, including in multivariate analysis adjusted on grade and molecular subtypes. LIV1-high tumors were associated with higher probabilities of sensitivity to hormone therapy and CDK4/6 inhibitors and lower probabilities of sensitivity to immune-checkpoint inhibitors and PARP inhibitors. These observations were different according to the molecular subtypes when analyzed separately. Conclusions: These results may provide novel insights into the clinical development and use of LIV1-targeted ADCs by identifying prognostic and predictive value of LIV1 expression in each molecular subtype and associated vulnerability to other systemic therapies.

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“…ADCs combine the cancer-targeting abilities of monoclonal antibodies with the delivery of highly cytotoxic drugs into tumor as a targeted chemotherapy ( 1 ). There are currently 3 ADCs approved for the treatment of breast cancer (BC); 2 of them: trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) for human epidermal growth factor receptor 2 (HER2) positive BC; and most recently sacituzumab govitecan (SG) for triple negative breast cancer (TNBC) ( 2 , 3 ).…”

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confidence: 99%

“…This could also represent a promising path for the future development of ADCs focusing on the creation of combinations to exploit the tumor microenvironment ( 3 ). Nowadays, different assays on the characterization of other types of anti-trop monoclonal antibodies are also under development for the detection of TROP2 in a wide variety of BC types ( 17 , 18 ) and may help refine the predictive value for drugs like SG.…”

mentioning

confidence: 99%

The role of sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer

Avila

Leone

2023

Ann Transl Med

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Sacituzumab govitecan in triple-negative breast cancer

Cited by 10 publications

References 31 publications

Delivery of Drugs into Cancer Cells Using Antibody–Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect

Delivery of Drugs into Cancer Cells Using Antibody–Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect

Prognostic and Predictive Value of LIV1 Expression in Early Breast Cancer and by Molecular Subtype

The role of sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer

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