Pertuzumab

Identification

Summary

Pertuzumab is an antineoplastic agent used in the treatment of HER2-positive metastatic breast cancer in combination with other antineoplastic agents.

Brand Names
Perjeta, Perjeta-Herceptin, Phesgo
Generic Name
Pertuzumab
DrugBank Accession Number
DB06366
Background

Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (subdomain II) of the human epidermal growth factor receptor 2 protein (HER2). It consists of two heavy chains and two lights chains that have 448 and 214 residues respectively. It was first approved by the FDA in 2012 for use with docetaxel and another HER2-targeted monoclonal antibody, trastuzumab, in the treatment of metastatic HER2-positive breast cancer. Its indicated conditions have since expanded to include use as both a neoadjuvant therapy and an adjuvant therapy in the treatment of HER2-positive breast cancers at high risk of recurrence.5,8

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db06366
Protein Chemical Formula
Not Available
Protein Average Weight
148000.0 Da
Sequences
>Amino acid sequence for pertuzumab light chain 
DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Amino acid sequence for pertuzumab heavy chain 
EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIY
NQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPG
Download FASTA Format
Synonyms
  • 2C4 Antibody
  • MOAB 2C4
  • Monoclonal Antibody 2C4
  • Pertuzumab
  • rhuMAb-2C4
External IDs
  • R1273
  • RG-1273

Pharmacology

Indication

Pertuzumab is indicated for intravenous administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.6 It is also indicated in combination with trastuzumab and other chemotherapies for the neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early-stage breast cancer as part of a complete treatment regimen6 and as adjuvant treatment in patients with HER2-positive early-stage breast cancer at high risk of recurrence.6

Pertuzumab is also indicated for subcutaneous injection - in combination with trastuzumab and hyaluronidase - in the treatment of HER2-positive breast cancers in adults.4

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Pertuzumab exerts its antineoplastic effects by binding to and inhibiting the activity of HER2, an oncogene that has been implicated in the formation of numerous cancers.6 As with other therapeutic monoclonal antibodies, pertuzumab has a relatively long duration of action necessitating dosing every 3 weeks.6 Drugs that block HER2 activity, including pertuzumab, have been implicated in the development of cardiotoxicity (specifically left ventricular dysfunction) - a baseline assessment of left ventricular ejection fraction (LVEF) should be conducted prior to beginning therapy with pertuzumab and at regular intervals throughout therapy to ensure LVEF remains within normal limits. Consider indefinite suspension of therapy if LVEF declines and does not improve.6

Mechanism of action

Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase receptor that plays an integral role in cell proliferation, differentiation, and survival. HER2 becomes active following dimerization with another HER2 receptor, another member of the HER protein family (e.g. HER3), or with a ligand - this dimer then phosphorylates and activates numerous intracellular signaling proteins, initiating signal transduction via pathways that include the Ras/mitogen-activated protein kinase pathway, the phosphatidylinositol 3' kinase (PI3K)/Akt pathway, and then Janus kinases/signal transducer and activator transcription pathway.2 HER2 is also a known oncogene - it is overexpressed or gene-amplified (i.e. HER2-positive) in approximately 20% of breast cancers and these cancers carry a generally poorer prognosis than HER2-negative breast cancers.2

Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2, thereby inhibiting ligand-initiated intracellular signaling via the MAP kinase and PI3K pathways. Inhibition of these pathways results in inhibition of cell growth and the initiation of apoptosis, respectively.5 Pertuzumab also appears to mediate antibody-dependent cell-mediated cytotoxicity.5

TargetActionsOrganism
AReceptor tyrosine-protein kinase erbB-2
binder
antibody
Humans
Absorption

Intravenously administered pertuzumab, given as a loading dose of 840mg followed by a maintenance dose of 420mg every 3 weeks, reaches steady-state concentration following the first maintenance dose.6 In its subcutaneous formulation, in combination with [hylauronidase], the absolute bioavailability of pertuzumab is approximately 0.7 and the median Tmax is 4 days.7 This subcutaneous formulation leverages the benefits of co-administration with hyaluronidase - this enzyme breaks down hylauronic acid, thereby decreasing the viscosity of the extracellular matrix (ECM) and allowing for greater bioavailability with subcutaneous administration.7

Volume of distribution

The average steady-state volume of distribution following intravenous administration is 3.53 - 7.5 L.6

Protein binding

Not Available

Metabolism

The metabolism of pertuzumab has not been studied directly. Monoclonal antibodies are typically subject to catabolism to smaller peptides and proteins prior to elimination.6

Route of elimination

Not Available

Half-life

The median half-life of pertuzumab was determined to be 18 days based on a population pharmacokinetic analysis.5

Clearance

The median clearance of pertuzumab was determined to be 0.24 L/day based on a population pharmacokinetic analysis.5

Adverse Effects
Adverseeffects
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Toxicity

There are no data regarding overdose of pertuzumab. Single doses higher than 25 mg/kg have not been tested.6 Symptoms of overdose are likely to be consistent with pertuzumab's adverse effect profile, and may therefore involve significant diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and/or peripheral neuropathy.5 Pertuzumab has been associated with the development of left ventricular dysfunction (i.e. cardiotoxicity) that may be exacerbated in instances of overdose.5

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 Pertuzumab.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Pertuzumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Pertuzumab.
AducanumabThe risk or severity of adverse effects can be increased when Pertuzumab is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Pertuzumab.
AlirocumabThe risk or severity of adverse effects can be increased when Pertuzumab is combined with Alirocumab.
AmivantamabThe risk or severity of adverse effects can be increased when Pertuzumab is combined with Amivantamab.
AmsacrineThe risk or severity of cardiotoxicity can be increased when Amsacrine is combined with Pertuzumab.
AnastrozoleThe risk or severity of cardiotoxicity can be increased when Anastrozole is combined with Pertuzumab.
AnifrolumabThe risk or severity of adverse effects can be increased when Pertuzumab is combined with Anifrolumab.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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International/Other Brands
Omnitarg / Perjeta
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PerjetaSolution420 mg / 14 mLIntravenousHoffmann La Roche2013-05-08Not applicableCanada flag
PerjetaInjection, solution, concentrate420 mgIntravenousRoche Registration Gmb H2016-09-08Not applicableEU flag
PerjetaInjection, solution, concentrate30 mg/1mLIntravenousGenentech, Inc.2012-06-08Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Perjeta-herceptinPertuzumab (420 mg / 14 mL) + Trastuzumab (440 mg / vial)Kit; Powder, for solution; SolutionIntravenousHoffmann La Roche2013-05-09Not applicableCanada flag
PhesgoPertuzumab (80 mg / mL) + Trastuzumab (40 mg / mL)SolutionSubcutaneousHoffmann La Roche2021-04-08Not applicableCanada flag
PhesgoPertuzumab (1200 mg) + Trastuzumab (600 mg)Injection, solutionSubcutaneousRoche Registration Gmb H2021-01-28Not applicableEU flag
PhesgoPertuzumab (600 mg/10mL) + Hyaluronidase (human recombinant) (2000 U/10mL) + Trastuzumab (600 mg/10mL)Injection, solutionSubcutaneousGenentech, Inc.2020-06-29Not applicableUS flag
PhesgoPertuzumab (60 mg / mL) + Trastuzumab (60 mg / mL)SolutionSubcutaneousHoffmann La Roche2021-04-09Not applicableCanada flag
PhesgoPertuzumab (600 mg) + Trastuzumab (600 mg)Injection, solutionSubcutaneousRoche Registration Gmb H2021-01-28Not applicableEU flag
PhesgoPertuzumab (1200 mg/15mL) + Hyaluronidase (human recombinant) (2000 U/15mL) + Trastuzumab (600 mg/15mL)Injection, solutionSubcutaneousGenentech, Inc.2020-06-29Not applicableUS flag

Categories

ATC Codes
L01XC13 — Pertuzumab
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
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
K16AIQ8CTM
CAS number
380610-27-5

References

Synthesis Reference

Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, McKeever K, Sliwkowski MX: Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 2006 Jun;55(6):717-27. doi: 10.1007/s00262-005-0058-x. Epub 2005 Sep 3.

General References
  1. Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, McKeever K, Sliwkowski MX: Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 2006 Jun;55(6):717-27. doi: 10.1007/s00262-005-0058-x. Epub 2005 Sep 3. [Article]
  2. Malenfant SJ, Eckmann KR, Barnett CM: Pertuzumab: a new targeted therapy for HER2-positive metastatic breast cancer. Pharmacotherapy. 2014 Jan;34(1):60-71. doi: 10.1002/phar.1338. Epub 2013 Aug 5. [Article]
  3. Pertuzumab protein sequence [Link]
  4. FDA News Release: FDA Approves Breast Cancer Treatment That Can Be Administered At Home By Health Care Professional [Link]
  5. FDA Approved Drug Products: Perjeta (pertuzumab) for intravenous injection [Link]
  6. Health Canada Product Monograph: Perjeta (pertuzumab) for intravenous injection [Link]
  7. FDA Approved Drug Products: Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) for subcutaneous injection [Link]
  8. FDA Drug Approvals: FDA grants regular approval to pertuzumab for adjuvant treatment of HER2-positive breast cancer [Link]
KEGG Drug
D05446
PubChem Substance
347910348
RxNav
1298944
ChEMBL
CHEMBL2007641
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Pertuzumab
FDA label
Download (362 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedDiagnosticBreast Cancer1
4CompletedTreatmentBreast Cancer1
4RecruitingTreatmentBreast Cancer / HER2/Neu-positive Breast Cancer / Malignant Neoplasm of Female Breast / Neoplasms, Breast1
3Active Not RecruitingTreatmentBreast Cancer3
3Active Not RecruitingTreatmentBreast Cancer / HER2/Neu Positive1
3Active Not RecruitingTreatmentEarly Breast Cancer1
3Active Not RecruitingTreatmentEstrogen Receptor Positive Breast Cancer / HER2/Neu-positive Breast Cancer1
3Active Not RecruitingTreatmentHER2-Positive Breast Carcinoma / Hormone Receptor-Positive Breast Carcinoma / Stage IB Breast Cancer AJCC v7 / Stage IIA Breast Cancer AJCC v6 and v7 / Stage IIB Breast Cancer AJCC v6 and v7 / Stage IIIA Breast Cancer AJCC v7 / Stage IIIB Breast Cancer AJCC v7 / Stage IIIC Breast Cancer AJCC v71
3Active Not RecruitingTreatmentHER2-Positive Early Stage Breast Cancer1
3Active Not RecruitingTreatmentHER2-positive Locally Advanced or Metastatic Breast Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous
Injection, solution, concentrateIntravenous
Injection, solution, concentrateIntravenous30 mg/1mL
Injection, solution, concentrateIntravenous420 mg
Injection, solution, concentrateIntravenous; Parenteral420 MG
SolutionIntravenous420 mg / 14 mL
Injection, solution, concentrateParenteral
Solution, concentrateIntravenous420 mg
SolutionIntravenous30 mg/ml
Kit; powder, for solution; solutionIntravenous
Injection, solutionSubcutaneous
SolutionSubcutaneous
Injection, solutionSubcutaneous1200 mg
Injection, solutionSubcutaneous600 mg
SolutionIntravenous420 mg/14ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2376596No2009-10-062020-06-23Canada flag
CA2579861No2012-12-182025-10-19Canada flag

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Antibody
General Function
Transmembrane signaling receptor activity
Specific Function
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, alt...
Gene Name
ERBB2
Uniprot ID
P04626
Uniprot Name
Receptor tyrosine-protein kinase erbB-2
Molecular Weight
137909.27 Da
References
  1. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX: Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004 Apr;5(4):317-28. [Article]
  2. FDA Approved Drug Products: Perjeta (pertuzumab) for intravenous injection [Link]

Drug created on March 19, 2008 16:27 / Updated on October 19, 2021 07:39