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| Primary information |
|---|
| ID | 14879 |
| Therapeutic ID | Th1548 |
| Protein Name | Sacituzumab govitecan |
| Sequence | NA
|
| Molecular Weight | NA |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | Sacituzumab govitecan has a mean half-life of 16 hours, while free SN-38 has a mean half-life of 18 hours.[L13002, A193731] |
| Description | Metastatic triple-negative breast cancer (mTNBC) is an aggressive form of breast cancer with limited treatment options involving cytotoxic chemotherapy agents.[A193653] Targeted chemotherapy through the application of antibody-conjugated agents (ADCs) is a recent advance in cancer treatment.[A193671] One such ADC is sacituzumab govitecan, which combines a humanized anti-trophoblast cell-surface antigen 2 (TROP-2) antibody with the topoisomerase I inhibitor SN-38.[L13002, A193674] Sacituzumab govitecan was granted FDA approval on April 22nd, 2020 and is marketed under the brand name Trodelvy™ by Immunomedics, Inc.; it is currently indicated under accelerated approval for the treatment of mTNBC patients who have undergone two or more prior therapies. As a targeted cytotoxic agent, it is hoped to provide similar efficacy with reduced adverse effects.[A193653] In November 2021, sacituzumab govitecan was also approved by the European Commission.[L39372] |
| Indication/Disease | Sacituzumab govitecan is indicated for adult patients with metastatic triple-negative breast cancer (mTNBC) who have undergone two or more prior therapies for metastatic disease.[L13002] Sacituzumab govitecan is also indicated for the treatment of locally advanced or metastatic urothelial cancer in adult patients who have received previous platinum-based therapy and either a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication has been approved under accelerated approval, and continued approval may be contingent on the demonstration of clinical benefit in confirmatory trials.[L13002] |
| Pharmacodynamics | Sacituzumab govitecan is a humanized monoclonal antibody/topoisomerase inhibitor conjugate designed to induce DNA damage-mediated cell death preferentially in TROP-2-expressing cancer cells. Detailed pharmacodynamic studies have not been performed for sacituzumab govitecan, although as a therapeutic protein, there is potential for immunogenicity. In addition, sacituzumab govitecan has the potential to cause severe hypersensitivity, nausea and vomiting, and embryo-fetal toxicity. Patients who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia.[L13002] |
| Mechanism of Action | Sacituzumab govitecan is an antibody-drug conjugate (ADC) targeting TROP-2-expressing cancer cells to induce DNA-damage-mediated cell death. The conjugate comprises a humanized anti-TROP-2 monoclonal antibody (RS7-3G11, also known as RS7) chemically linked by a hydrolyzable CL2A linker to the cytotoxic drug SN-38.[L13002, A193662] The proposed mechanism of action first involves the binding of the RS7 component to TROP-2, which is highly expressed on the cell surface of multiple cancers.[A193671] Binding of RS7 to TROP-2 results in rapid internalization of bound antibody[A193656, A193659], and the likely intracellular release of SN-38 via hydrolysis of the CL2A linker[L13002, A193674]. SN-38 is an active metabolite of the anti-cancer drug [irinotecan], which is thought to work primarily through inhibition of DNA topoisomerase I, leading to DNA damage and eventual cell death.[A193665] In addition, recent work has identified a possible secondary mechanism of action for SN-38 by disrupting the binding of Far Upstream Binding Protein 1 (FUBP1) to the _FUSE_ elements regulating oncogene expression.[A193668] In addition to SN-38-mediated cell death, there is also some evidence that the RS7 component of the conjugate drug possesses antibody-directed cellular toxicity.[A193674, A193662] |
| Toxicity | Toxicity information regarding sacituzumab govitecan is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as neutropenia, diarrhea, hypersensitivity, nausea/vomiting, and other systemic effects related to cytotoxic drugs. Symptomatic and supportive measures are recommended.[L13002] |
| Metabolism | The metabolism of sacituzumab govitecan has not been extensively studied. The SN-38 moiety is known to undergo O-glucuronidation by UGT1A1, presumably in the liver, and the SN-38 glucuronide metabolite SN-38G is found in the serum of patients undergoing treatment.[L13002, A193665] |
| Absorption | In patients receiving 10 mg/kg sacituzumab govitecan the Cmax of the conjugate was 243,000 ± 45,600 ng/mL while the Cmax of free SN-38 was 127 ± 60 ng/mL. Similarly, the AUC0-168 for the conjugate/free SN-38 was 5,210,000 ± 1,230,000 and 3,900 ± 1,830 ng |
| Sacituzumab govitecan has a mean volume of distribution of 0.045 L/kg.[L13002] |
| Clearance | Sacituzumab govitecan has a clearance rate of 0.002 L/h/kg.[L13002] |
| Categories | Topoisomerase Inhibitors |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Tumor-associated calcium signal transducer 2,DNA topoisomerase 1,Far upstream element-binding protein 1 |
| Brand Name | NA |
| Company | NA |
| Brand Description | NA |
| Prescribed For | NA |
| Chemical Name | NA |
| Formulation | NA |
| Physical Appearance | NA |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | (2R)-2-amino-3-[1-[[4-[[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[2-[[(2S)-6-amino-1-[4-[[(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl]oxycarbonyloxymethyl]anilino]-1-oxohexan-2-yl]amino]-2-oxoethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylcarbamoyl]cyclohexyl]methyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |