Trodelvy® (sacituzumab govitecan-hziy)
Mechanism of Action
Gilead Sciences, Inc. is providing this document to you, a US Healthcare Professional, in response to your unsolicited request for medical information.
Gilead Sciences, Inc. is providing this document to you, a US Healthcare Professional, in response to your unsolicited request for medical information.
Trodelvy® (sacituzumab govitecan-hziy)
Mechanism of Action
Some data may be outside of the US FDA-approved prescribing information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA-approved prescribing information.
The full indication, important safety information, and boxed warnings for neutropenia and diarrhea are available at:
www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.
Relevant Product Labeling1
Mechanism of Action
SG is a trophoblast cell‑surface antigen-2 (Trop-2)-directed antibody-drug conjugate (ADC). Sacituzumab is a humanized antibody that recognizes Trop-2. The small molecule that is the active metabolite of irinotecan (SN-38), is a topoisomerase I (TOP1) inhibitor, which is covalently attached to the antibody by a linker. Pharmacology data suggest that SG binds to Trop-2-expressing cancer cells and is internalized with the subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with TOP1 and prevents re-ligation of TOP1-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death. SG decreased tumor growth in mouse xenograft models of triple‑negative breast cancer.
SG Mechanism of Action
SG is an ADC made from a humanized anti-Trop-2 monoclonal antibody (hRS7) conjugated with SN-38 via a hydrolysable linker (CL2A) with a drug-to-antibody ratio of 7.6:1.2-5 Trop-2 is a transmembrane protein frequently expressed by many cancers.2-9 The antibody component of SG binds to Trop-2 expressed on the tumor cell surface. The Trop-2-bound antibody complex is internalized, enabling SG to concentrate within the Trop-2 expressing tumor cells.2-5 The Trop-2-bound antibody complex is then trafficked intracellularly to lysosomes.4 The linker connecting the antibody to SN-38 is cleaved upon exposure to environments with low pH, followed by hydrolysis of the linker within the lysosome. The free SN-38 is released intracellularly.4,5 SN-38 is a TOP1 inhibitor that prevents re‑ligation of TOP1-induced single strand breaks resulting in DNA damage, apoptosis, and cell death.2-5
Bystander Effect
Based on preclinical data, it is hypothesized that given its membrane-permeable nature, free SN-38 can leave the cell once the internalization of the Trop-2-bound antibody complex process has been completed.4,10 The SN-38 payload was observed in cells distal to blood vessels in the tumor in the absence of detectable levels of the ADC backbone. In addition, after 48 hours, SN-38 was distributed in the tumor in a homogeneous pattern consistent with distribution of SN-38 via the bystander effect to cells lacking expression of Trop-2.10 See Figure 1 below.
Figure 1. SG Mechanism of Action4
Note: 1=binding; 2=internalization; 3=intracellular trafficking; 4=lysosomal degradation; 5=cell toxicity; 6=bystander effect.
References
1. TRODELVY® Gilead Sciences Inc. Trodelvy (sacituzumab govitecan-hziy) for injection, for intravenous use. U.S. Prescribing Information. Foster City, CA.
3. Goldenberg DM, Sharkey RM. Sacituzumab govitecan, a novel, third-generation, antibody-drug conjugate (ADC) for cancer therapy. Expert Opin Biol Ther. 2020;20(8):871-885. https://www.ncbi.nlm.nih.gov/pubmed/32301634
6. Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015;6(3-4):84-105. https://www.ncbi.nlm.nih.gov/pubmed/26000093
Product Label
For the full indication, important safety information, and boxed warning(s), please refer to the Trodelvy US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.
Follow Up
For any additional questions, please contact Trodelvy Medical Information at:
☎ 1-888-983-4668 or www.askgileadmedical.com
Adverse Event Reporting
Please report all adverse events to:
Gilead Global Patient Safety ☎ 1-800-445-3235, option 3 or
https://www.gilead.com/utility/contact/report-an-adverse-event
FDA MedWatch Program by ☎ 1-800-FDA-1088 or MedWatch, FDA, 5600 Fishers Ln, Rockville, MD 20852 or www.accessdata.fda.gov/scripts/medwatch
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