Sacituzumab govitecan
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Identification
- Summary
Sacituzumab govitecan is sacituzumab govitecan targets TROP-2-expressing cancer cells through a humanized antibody (RS7) before subsequently becoming internalized and releasing the topoisomerase I inhibitor SN-38 to induce DNA damage-mediated apoptosis.
- Brand Names
- Trodelvy
- Generic Name
- Sacituzumab govitecan
- DrugBank Accession Number
- DB12893
- Background
Metastatic triple-negative breast cancer (mTNBC) is an aggressive form of breast cancer with limited treatment options involving cytotoxic chemotherapy agents.1 Targeted chemotherapy through the application of antibody-conjugated agents (ADCs) is a recent advance in cancer treatment.7 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-38.10,8
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.1 In November 2021 and July 20 2023, sacituzumab govitecan was also approved by the European Commission and Health Canada respectively.11,14
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
- Not Available
- Synonyms
- Sacituzumab govitecan
- sacituzumab govitecan-hziy
- External IDs
- hRS 7SN38
- hRS7-SN38
- IMMU 132
- IMMU-132
Pharmacology
- Indication
Sacituzumab govitecan is indicated for adult patients with unresectable locally-advanced or metastatic triple-negative breast cancer (mTNBC) who have undergone two or more prior therapies for metastatic disease by the FDA, Health Canada, and EMA.12,13,15 It is also indicated for the treatment of unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.12,13,15 These indications are approved in the US, Canada, and Europe.
In the US, sacituzumab govitecan is additionally 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.10
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Hormone receptor positive metastatic breast cancer •••••••••••• ••••• ••••• ••••••••• •••••••• •• ••••• •••••••• ••••••••• •••••••••• ••••••• •••••••••••• ••• •••••••• Treatment of Locally advanced or metastatic urothelial carcinoma (uc) •••••••••••• ••••• •••••••• ••••••• •••• •••••••••• ••••• •••••••••• •••••• •• •••••••••• •••••••••••• • ••••••• •••••••••• •••••••• •••••••• ••••• ••••••• ••••••••• Treatment of Metastatic triple negative breast cancers •••••••••••• ••••• •• ••••• •••••••• ••••••••• •••••••••• ••••••• •••••••••••• ••• •••••••• Treatment of Metastatic triple negative breast cancers •••••••••••• ••••• •• ••••• •••••••• ••••••••• ••••••••• Treatment of Metastatic triple-negative breast cancer •••••••••••• ••••• •••••••• •••••••••• •••••••••••• ••••••••• - Contraindications & Blackbox Warnings
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- 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.10
- 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-38.10,4
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.7 Binding of RS7 to TROP-2 results in rapid internalization of bound antibody2,3, and the likely intracellular release of SN-38 via hydrolysis of the CL2A linker10,8. 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.5 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.6
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.8,4
Target Actions Organism ATumor-associated calcium signal transducer 2 antibodyHumans ADNA topoisomerase 1 inhibitorHumans UFar upstream element-binding protein 1 inhibitorHumans - 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*h/mL, respectively.10
- Volume of distribution
Sacituzumab govitecan has a mean volume of distribution of 0.045 L/kg.10
- Protein binding
SN-38, the active moiety, remains mostly bound to the IgG component in serum. In patients administered with 10 mg/kg of sacituzumab govitecan, free SN-38 serum levels were measured as 2.3% and 4.5% at 30 minutes and one day, respectively.9
- 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.10,5
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- Route of elimination
No detailed information exists for sacituzumab govitecan elimination; renal elimination of SN-38 is known to be minimal, and it is expected that the fecal route will be the major contributor.10,5
- Half-life
Sacituzumab govitecan has a mean half-life of 16 hours, while free SN-38 has a mean half-life of 18 hours.10,9
- Clearance
Sacituzumab govitecan has a clearance rate of 0.002 L/h/kg.10
- Adverse Effects
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- 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.10
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Sacituzumab govitecan. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Sacituzumab govitecan. Adenine The serum concentration of Sacituzumab govitecan can be increased when it is combined with Adenine. Aducanumab The risk or severity of adverse effects can be increased when Aducanumab is combined with Sacituzumab govitecan. Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Sacituzumab govitecan. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Trodelvy Powder, for solution 180 mg/1 Intravenous Gilead Sciences 2020-04-22 Not applicable US Trodelvy Injection, powder, for solution 200 mg Intravenous Gilead Sciences Ireland Uc 2022-05-04 Not applicable EU Trodelvy Powder, for solution 180 mg / vial Intravenous Gilead Sciences 2021-11-22 Not applicable Canada
Categories
- ATC Codes
- L01FX17 — Sacituzumab govitecan
- Drug Categories
- Alkaloids
- Amino Acids, Peptides, and Proteins
- Antibodies
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antibody-drug Conjugates
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Blood Proteins
- Cancer immunotherapy
- Globulins
- Immunoglobulins
- Immunologic Factors
- Immunoproteins
- Immunotherapy
- Monoclonal antibodies and antibody drug conjugates
- Noxae
- Proteins
- Serum Globulins
- Topoisomerase Inhibitors
- Toxic Actions
- Trop-2-Directed Monoclonal Antibodies
- UGT1A1 Substrates
- Chemical TaxonomyProvided by Classyfire
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- M9BYU8XDQ6
- CAS number
- 1491917-83-9
References
- Synthesis Reference
Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM: Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011 May 15;17(10):3157-69. doi: 10.1158/1078-0432.CCR-10-2939. Epub 2011 Mar 3.
- General References
- Zangardi ML, Spring LM, Nagayama A, Bardia A: Sacituzumab for the treatment of triple-negative breast cancer: the poster child of future therapy? Expert Opin Investig Drugs. 2019 Feb;28(2):107-112. doi: 10.1080/13543784.2019.1555239. Epub 2018 Dec 17. [Article]
- Stein R, Basu A, Chen S, Shih LB, Goldenberg DM: Specificity and properties of MAb RS7-3G11 and the antigen defined by this pancarcinoma monoclonal antibody. Int J Cancer. 1993 Dec 2;55(6):938-46. doi: 10.1002/ijc.2910550611. [Article]
- Shih LB, Xuan H, Aninipot R, Stein R, Goldenberg DM: In vitro and in vivo reactivity of an internalizing antibody, RS7, with human breast cancer. Cancer Res. 1995 Dec 1;55(23 Suppl):5857s-5863s. [Article]
- Goldenberg DM, Stein R, Sharkey RM: The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018 Jun 22;9(48):28989-29006. doi: 10.18632/oncotarget.25615. eCollection 2018 Jun 22. [Article]
- Bailly C: Irinotecan: 25 years of cancer treatment. Pharmacol Res. 2019 Oct;148:104398. doi: 10.1016/j.phrs.2019.104398. Epub 2019 Aug 12. [Article]
- Khageh Hosseini S, Kolterer S, Steiner M, von Manstein V, Gerlach K, Trojan J, Waidmann O, Zeuzem S, Schulze JO, Hahn S, Steinhilber D, Gatterdam V, Tampe R, Biondi RM, Proschak E, Zornig M: Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE. Biochem Pharmacol. 2017 Dec 15;146:53-62. doi: 10.1016/j.bcp.2017.10.003. Epub 2017 Oct 13. [Article]
- Ponde N, Aftimos P, Piccart M: Antibody-Drug Conjugates in Breast Cancer: a Comprehensive Review. Curr Treat Options Oncol. 2019 Apr 1;20(5):37. doi: 10.1007/s11864-019-0633-6. [Article]
- Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM: Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011 May 15;17(10):3157-69. doi: 10.1158/1078-0432.CCR-10-2939. Epub 2011 Mar 3. [Article]
- Ocean AJ, Starodub AN, Bardia A, Vahdat LT, Isakoff SJ, Guarino M, Messersmith WA, Picozzi VJ, Mayer IA, Wegener WA, Maliakal P, Govindan SV, Sharkey RM, Goldenberg DM: Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics. Cancer. 2017 Oct 1;123(19):3843-3854. doi: 10.1002/cncr.30789. Epub 2017 May 30. [Article]
- FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]
- BioSpace News Release: Trodelvy® (sacituzumab govitecan) Granted European Commission Marketing Authorization for Treatment of Metastatic Triple-Negative Breast Cancer in Second Line [Link]
- FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) for intravenous injection (February 2023) [Link]
- Health Canada Approved Drug Proucts: TRODELVY (sacituzumab govitecan) lyophilized powder for solution for injection, for intravenous use [Link]
- HEALTH CANADA APPROVES TRODELVY® (SACITUZUMAB GOVITECAN) IN PRE-TREATED HR+/HER2- METASTATIC BREAST CANCER [Link]
- EMA Approved Drug Products: Trodelvy (sacituzumab govitecan) for intravenous injection [Link]
- External Links
- PubChem Substance
- 347911403
- 2360232
- Wikipedia
- Sacituzumab_govitecan
- FDA label
- Download (792 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Breast Cancer / Metastatic Cancer 1 somestatus stop reason just information to hide Not Available Approved for Marketing Not Available Metastatic Triple Negative Breast Cancers 1 somestatus stop reason just information to hide Not Available Recruiting Not Available Breast Cancer 1 somestatus stop reason just information to hide 4 Enrolling by Invitation Treatment Metastatic Solid Neoplasm 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Carcinoma Breast Stage IV / Locally Advanced or Unresectable Metastatic Breast Cancer 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 200 mg Powder, for solution Intravenous 180 mg / vial Powder, for solution Intravenous 180 mg/1 Injection Parenteral 200 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antibody
- Curator comments
- The RS7 monoclonal antibody component of sacituzumab govitecan binds to TROP-2, allowing for the conjugate to be internalized into target cells.
- General Function
- May function as a growth factor receptor
- Specific Function
- Not Available
- Gene Name
- TACSTD2
- Uniprot ID
- P09758
- Uniprot Name
- Tumor-associated calcium signal transducer 2
- Molecular Weight
- 35709.02 Da
References
- Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM: Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011 May 15;17(10):3157-69. doi: 10.1158/1078-0432.CCR-10-2939. Epub 2011 Mar 3. [Article]
- FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- SN-38-mediated inhibition of DNA topoisomerase I is thought to be the main mechanism of action.
- General Function
- Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the BMAL1 promoter
- Specific Function
- ATP binding
- Gene Name
- TOP1
- Uniprot ID
- P11387
- Uniprot Name
- DNA topoisomerase 1
- Molecular Weight
- 90725.19 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- The clinical relevance of FUBP1 inhibition is currently not known.
- General Function
- Regulates MYC expression by binding to a single-stranded far-upstream element (FUSE) upstream of the MYC promoter. May act both as activator and repressor of transcription
- Specific Function
- mRNA binding
- Gene Name
- FUBP1
- Uniprot ID
- Q96AE4
- Uniprot Name
- Far upstream element-binding protein 1
- Molecular Weight
- 67560.205 Da
References
- Khageh Hosseini S, Kolterer S, Steiner M, von Manstein V, Gerlach K, Trojan J, Waidmann O, Zeuzem S, Schulze JO, Hahn S, Steinhilber D, Gatterdam V, Tampe R, Biondi RM, Proschak E, Zornig M: Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE. Biochem Pharmacol. 2017 Dec 15;146:53-62. doi: 10.1016/j.bcp.2017.10.003. Epub 2017 Oct 13. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1A1
- Molecular Weight
- 59590.91 Da
References
- FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]
Drug created at October 21, 2016 01:04 / Updated at August 19, 2023 10:38