Sacituzumab marketed by the brand name of Trodelvy (Gilead Sciences) is FDA approved for the treatment of patients with advanced breast cancer and urothelial cancer. Trodelvy mechanism of action in the treatment of these cancers is a little complicated to understand. It is therefore important to define a few terminologies before discussing the MOA of Sacituzumab (Trodelvy).
- It is the antibody that is directed against a specific antigen made from cloning one specific white blood cell. Unlike polyclonal antibodies that are produced by different white blood cells, all monclonal antibodies can be traced back to one parent white blood cell.
Antibody-Drug Conjugate (ADC):
- ADC is a new class of biological medicines that are highly targeted. The antibody acts as a carrier for the drug that has been attached to it. Monoclonal antibodies target a specific cell (cancer cell) and attach to the antigen. The drug is then released to act on that specific cell, hence, sparing the normal cells. ADC Biological medicines are highly toxic to the target cells but have little systemic toxicity.
- TROP-2 is a protein that was first identified in human trophoblastic cells. It was believed that these proteins are responsible for the growth and invasion of tumor cells. It is highly expressed in cancer cells of the breast, stomach, pancreas, lung, colon, cervix, ovaries, and head and neck cancers. “Trophoblast cell-surface antigen, or Trop-2”, is also known as tumor-associated calcium signal transducer (TACSTD2), epithelial glycoprotein-1 (EGP-1), gastrointestinal tumor-associated antigen (GA733-1), and surface marker 1 (M1S1) [Ref].
- SN-38 is the active metabolite of irinotecan and is believed to be 1000 times more potent than the parent drug. It inhibits the enzyme topoisomerase-1 that cuts a DNA strand and is responsible for transcription, translation, and correcting DNA errors.
Trodelvy Mechanism of Action (Sacituzumab MOA):
Trodelvy (Sacituzumab Govitecan) is an ADC (antibody-drug conjugate). The monoclonal antibody is directed against TROP-2 antigens. TROP-2 antigens are transmembrane proteins highly expressed in tumor cells. After binding to the cells expressing the TROP-2 antigens, the ADC is internalized. SN-38, the active metabolite of irinotecan, a topoisomerase inhibitor is released inside the cells.
SN-38 inhibits topoisomerase 1, preventing DNA repair, causing DNA damage, and inducing cellular apoptosis [Ref].
Trodelvy (Sacituzumab Govitecan) Indications:
Trodelvy (Sacituzumab Govitecan) is FDA approved for the treatment of patients with advanced, unresectable, metastatic, relapsed, or refractory triple-negative breast cancer. Triple-negative breast cancers do not express estrogen, progesterone, and excess human epidermal growth factor receptor 2 (HER-2) proteins. It is recommended in adults who have received two or more systemic therapies including at least one treatment for metastatic breast cancer.
Trodelvy (Sacituzumab Govitecan) is also FDA approved for the treatment of patients with metastatic or locally advanced urothelial carcinoma in patients who have been previously treated with platinum-based chemotherapeutic drugs and immune-checkpoint inhibitors (programmed death receptor-1 inhibitor PD-1 or programmed death-ligand 1 inhibitor such as pembrolizumab).