Sacituzumab govitecan

Identification

Name
Sacituzumab govitecan
Accession Number
DB12893
Description

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

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 metastatic triple-negative breast cancer (mTNBC) who have undergone two or more prior therapies for metastatic disease.10

This indication has been approved under accelerated approval, and continued approval may be contingent on the demonstration of clinical benefit in confirmatory trials.10

Associated Conditions
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

TargetActionsOrganism
ATumor-associated calcium signal transducer 2
antibody
Humans
ADNA topoisomerase 1
inhibitor
Humans
UFar upstream element-binding protein 1
inhibitor
Humans
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

Affected organisms
  • Humans and other mammals
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.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Sacituzumab govitecan.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Sacituzumab govitecan.
AdenineThe serum concentration of Sacituzumab govitecan can be increased when it is combined with Adenine.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Sacituzumab govitecan.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Sacituzumab govitecan.
AmitriptylineThe serum concentration of Sacituzumab govitecan can be increased when it is combined with Amitriptyline.
Anthrax immune globulin humanThe risk or severity of adverse effects can be increased when Anthrax immune globulin human is combined with Sacituzumab govitecan.
Antilymphocyte immunoglobulin (horse)The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Sacituzumab govitecan.
Antithymocyte immunoglobulin (rabbit)The risk or severity of adverse effects can be increased when Antithymocyte immunoglobulin (rabbit) is combined with Sacituzumab govitecan.
Asfotase alfaThe risk or severity of adverse effects can be increased when Asfotase alfa is combined with Sacituzumab govitecan.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TrodelvyPowder, for solution180 mg/1IntravenousImmunomedics, Inc.2020-04-22Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

Drug Categories
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

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
  1. 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. [PubMed:30507322]
  2. 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. [PubMed:8253531]
  3. 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. [PubMed:7493360]
  4. 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. [PubMed:29989029]
  5. 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. [PubMed:31415916]
  6. 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. [PubMed:29031818]
  7. 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. [PubMed:30931493]
  8. 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. [PubMed:21372224]
  9. 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. [PubMed:28558150]
  10. FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]
PubChem Substance
347911403
RxNav
2360232
Wikipedia
Sacituzumab_govitecan
FDA label
Download (792 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentBreast Cancer1
3Enrolling by InvitationTreatmentMetastatic Cancers / Tumors, Solid1
3Not Yet RecruitingTreatmentCancer, Bladder / Locally Advanced Urothelial Cancer / Transitional Cell Carcinoma / Urothelial carcinoma ureter metastatic1
3RecruitingTreatmentMetastatic Breast Cancer1
2Not Yet RecruitingTreatmentGlioblastomas1
2Not Yet RecruitingTreatmentHER2 Negative Breast Cancer / HER2-Negative Breast Cancer / HR-positive Breast Cancer / Invasive Breast Cancer / Metastatic Breast Cancer1
2Not Yet RecruitingTreatmentMetastatic Triple-negative Breast Cancer1
2RecruitingTreatmentBreast Cancer / PD-L1 negative / Triple Negative Breast Cancer (TNBC)1
2RecruitingTreatmentEndometrial Carcinoma1
2RecruitingTreatmentER-Negative Breast Cancer / HER2 Negative Breast Cancer / HER2-Negative Breast Cancer / Invasive Breast Cancer / PR-Negative Breast Cancer / Triple Negative Breast Cancer (TNBC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Powder, for solutionIntravenous180 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
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
  1. 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. [PubMed:21372224]
  2. 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
Poly(a) rna binding
Specific 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 singl...
Gene Name
TOP1
Uniprot ID
P11387
Uniprot Name
DNA topoisomerase 1
Molecular Weight
90725.19 Da
References
  1. 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. [PubMed:31415916]
  2. FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
The clinical relevance of FUBP1 inhibition is currently not known.
General Function
Transcriptional activator activity, rna polymerase ii distal enhancer sequence-specific binding
Specific 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.
Gene Name
FUBP1
Uniprot ID
Q96AE4
Uniprot Name
Far upstream element-binding protein 1
Molecular Weight
67560.205 Da
References
  1. 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. [PubMed:29031818]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: Trodelvy (sacituzumab govitecan-hziy) injection [Link]

Drug created on October 20, 2016 19:04 / Updated on June 12, 2020 10:53

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