Identification

Name
Trastuzumab emtansine
Accession Number
DB05773
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Trastuzumab emtansine, formerly called Trastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody drug conjugate (ADC) comprised of Genentech's trastuzumab antibody linked to ImmunoGen's cell-killing agent, DM1. T-DM1 combines two strategies-- anti-HER2 activity and targeted intracellular delivery of the potent anti-microtubule agent, DM1 (a maytansine derivative)--to produce cell cycle arrest and apoptosis. Trastuzumab emtansine is marketed under the brand name Kadcyla and is indicated for use in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment. The FDA label has two precautions. First that trastuzumab emtansine and trastuzumab cannot be interchanged. Second that there is a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.

Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • Ado-trastuzumab
  • Ado-trastuzumab emtansine
  • T-DM1
  • Trastuzumab emtansine
  • Trastuzumab-DM1
  • Trastuzumab-MCC-DM1
External IDs
PRO-132365 / PRO132365 / RG-3502
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
KadcylaPowder, for solution100 mgIntravenousHoffmann La Roche2013-10-09Not applicableCanada
KadcylaInjection, powder, lyophilized, for solution20 mg/1mLIntravenousGenentech, Inc.2013-02-22Not applicableUs
KadcylaPowder, for solution160 mgIntravenousHoffmann La RocheNot applicableNot applicableCanada
KadcylaInjection, powder, lyophilized, for solution20 mg/1mLIntravenousGenentech, Inc.2013-02-22Not applicableUs
Categories
UNII
SE2KH7T06F
CAS number
1018448-65-1

Pharmacology

Indication

Used in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment.

Associated Conditions
Pharmacodynamics

Trastuzumab emtansine was evaluated in two Herceptin-responsive and one Herceptin-resistant breast tumor models. In the Herceptin-responsive models, Trastuzumab-DM1 caused complete tumor regression in all mice, whereas Herceptin alone slowed tumor growth. In the Herceptin- resistant model, Herceptin alone had no effect on tumor growth. In contrast, Trastuzumab-DM1 caused >90% tumor reduction in all mice. In this Herceptin- resistant model, tumor regrowth was observed after cessation of Trastuzumab- DM1 treatment, yet regression re-occurred when dosing was resumed. The effect was specific for HER2-positive tumors. Thus the physiological effects of trastuzumab emtansine are cell cycle arrest and cell death by apoptosis.

Mechanism of action

Trastuzumab emtansine is a HER2 antibody drug conjugate. The antibody portion is trastuzumab, which is humanized anti-HER2 IgG1, and produced in the mammalian Chinese Hamster Ovary cells. The drug portion is DM1, which is a maytansine derivative that inhibits microtubules. These two portions are covalently connected by 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (MCC), which is a stable thioether linker. Together MCC and DM1 are called emtansine and are produced by chemical synthesis. Trastuzumab emtansine binds to the HER2 receptor’s sub-domain IV and goes into the cell by receptor-mediated endocytosis. Lysosomes degrade trastuzumab emtansine and release DM1. DM1 binds to tubulin in microtubules and inhibits microtubule function producing cell arrest and apoptosis. As well, similar to trastuzumab, in vitro studies have shown that both HER2 receptor signalling inhibition and antibody-dependent cytotoxicity are mediated by trastuzumab emtansine.

TargetActionsOrganism
AReceptor tyrosine-protein kinase erbB-2
antibody
Human
Absorption

The absorption/ bioavailability should be close to 100% since trastuzumab emtansine is administered IV.

Volume of distribution

The volume of distribution of trastuzumab emtansine is about 3.13 L.

Protein binding

DM1 has a plasma protein binding value of 93%.

Metabolism

Trastuzumab emtansine undergoes lysosomal degradation to MCC-DM1, Lys-MCC-DM1, and DM1. All of these products are detected at low levels in the plasma. DM1 undergoes further degradation by CYP3A4 and CYP3A5, but DM1 does not induce or inhibit any of the CYP450 enzymes.

Route of elimination

The route of elimination has not yet been fully elucidated.

Half life

Trastuzumab emtansine has a long half life of about 4 days.

Clearance

After IV infusion, trastuzumab emtansine has a clearance of 0.68 L/day.

Toxicity

The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Trastuzumab emtansine is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Trastuzumab emtansine is combined with (S)-Warfarin.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Trastuzumab emtansine.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Trastuzumab emtansine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Trastuzumab emtansine.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Trastuzumab emtansine.
6-Deoxyerythronolide BThe metabolism of Trastuzumab emtansine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Trastuzumab emtansine.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Trastuzumab emtansine is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Trastuzumab emtansine.
Food Interactions
Not Available

References

General References
  1. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX: Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008 Nov 15;68(22):9280-90. doi: 10.1158/0008-5472.CAN-08-1776. [PubMed:19010901]
External Links
KEGG Drug
D09980
PubChem Substance
347910224
ChEMBL
CHEMBL1743082
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Trastuzumab_emtansine
ATC Codes
L01XC14 — Trastuzumab emtansine
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (428 KB)
MSDS
Download (381 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentHER2 Positive Breast Cancers1
1Active Not RecruitingTreatmentHER2 Positive Breast Cancers / Her2-negative Metastatic Breast Cancer / HER2-positive Metastatic Breast Cancer / Locally Advanced or Early Breast Cancer1
1Active Not RecruitingTreatmentHER2/Neu Positive / Recurrent Breast Carcinoma / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer1
1Active Not RecruitingTreatmentHer2-Positive Breast Cancer / Recurrent Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer1
1Active Not RecruitingTreatmentMetastatic Breast Cancer (MBC)1
1CompletedTreatmentCancer, Breast2
1CompletedTreatmentMetastatic Breast Cancer (MBC)2
1CompletedTreatmentNeoplasms, Breast1
1RecruitingTreatmentAdvanced Breast Cancer1
1RecruitingTreatmentCancer, Breast3
1RecruitingTreatmentHER2 Positive Breast Carcinoma / Recurrent Breast Carcinoma / Stage III Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer1
1RecruitingTreatmentMetastatic Breast Cancer (MBC) / Recurrent Breast Cancer1
1, 2CompletedTreatmentMetastatic Breast Cancer (MBC)2
1, 2RecruitingTreatmentBrain Cancer / Brain Metastasis / Cancer, Breast1
1, 2RecruitingTreatmentBreast Cancer Metastatic / Her2-Positive Breast Cancer1
1, 2RecruitingTreatmentCancer, Breast2
1, 2TerminatedTreatmentCancer, Advanced / Cancer, Breast / Colorectal Cancers / Esophageal Cancers / Malignant Neoplasm of Stomach1
1, 2TerminatedTreatmentCancer, Breast / Metastatic Breast Cancer (MBC)1
2Active Not RecruitingDiagnosticHER-2 Positive Breast Cancer1
2Active Not RecruitingTreatmentCancer, Breast3
2Active Not RecruitingTreatmentEstrogen Receptor Negative / Estrogen Receptor Status / HER2 Positive Breast Carcinoma / Progesterone Receptor Negative / Progesterone Receptor Status / Stage I Breast Cancer AJCC v7 / Stage I Breast Carcinoma / Stage IA Breast Cancer / Stage IA Breast Cancer AJCC v7 / Stage IB Breast Cancer / Stage IB Breast Cancer AJCC v7 / Stage II Breast Cancer / Stage II Breast Cancer AJCC v6 and v7 / Stage IIA Breast Cancer / Stage IIA Breast Cancer AJCC v6 and v7 / Stage IIB Breast Cancer / Stage IIB Breast Cancer AJCC v6 and v7 / Stage III Breast Cancer / Stage III Breast Cancer AJCC V7 / Stage IIIA Breast Cancer / Stage IIIA Breast Cancer AJCC v7 / Stage IIIB Breast Cancer / Stage IIIB Breast Cancer AJCC v7 / Stage IIIC Breast Cancer / Stage IIIC Breast Cancer AJCC v71
2Active Not RecruitingTreatmentMetastatic Breast Cancer (MBC)2
2CompletedTreatmentBladder Cancer, Pancreas Cancer, Cholangiocellular Carcinoma / Bladder Cancers / Cholangiocellular Carcinoma / Malignant Neoplasm of Pancreas1
2CompletedTreatmentBreast Cancer, Gastric Cancer / Tumors, Solid1
2CompletedTreatmentCancer, Breast2
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2CompletedTreatmentMetastatic Breast Cancer (MBC)3
2Not Yet RecruitingTreatmentBreast Cancer Stage / Cancer, Breast / HER2 Positive Breast Carcinoma / Her2-Positive Breast Cancer / Metastatic Breast Cancer (MBC) / Recurrent Breast Cancer1
2Not Yet RecruitingTreatmentMetastatic HER2-positive Breast Cancer With Brain Metastasis1
2RecruitingTreatmentAdvanced Malignant Neoplasm / Advanced Malignant Solid Neoplasm / Bladder Carcinoma / Carcinoma, Breast / Carcinoma, Colorectal / Carcinoma, Pancreatic / Cervical Carcinoma / Colon Carcinoma / Endometrial Carcinoma / Gastric Carcinoma / Gliomas / Head and Neck Carcinoma / Liver and Intrahepatic Bile Duct Carcinoma / Lung, Carcinoma / Malignant Lymphomas / Malignant Uterine Neoplasm / Melanoma / Oesophageal Carcinoma / Ovarian Carcinoma / Plasma Cell Myeloma / Prostate Cancer / Rectal Carcinoma / Recurrent Bladder Carcinoma / Recurrent Breast Carcinoma / Recurrent Cervical Carcinoma / Recurrent Colon Carcinoma / Recurrent Colorectal Carcinoma / Recurrent Esophageal Carcinoma / Recurrent Gastric Carcinoma / Recurrent Gliomas / Recurrent Head and Neck Carcinoma / Recurrent Liver Carcinoma / Recurrent Lung Carcinoma / Recurrent Lymphoma / Recurrent Malignant Solid Neoplasm / Recurrent Melanoma / Recurrent Ovarian Carcinoma / Recurrent Pancreatic Carcinoma / Recurrent Plasma Cell Myeloma / Recurrent Prostate Carcinoma / Recurrent Rectal Carcinoma / Recurrent Skin Carcinoma / Recurrent Solid Neoplasm / Recurrent Thyroid Gland Carcinoma / Recurrent Uterine Corpus Carcinoma / Refractory Lymphomas / Refractory Malignant Neoplasm / Refractory Malignant Solid Neoplasm / Refractory Plasma Cell Myeloma / Renal Carcinoma / Skin Carcinoma / Solid Neoplasms / Thyroid Gland Carcinoma / Uterine Corpus Cancer1
2RecruitingTreatmentBladder Cancers / Lung Cancers / Solid Tumor Cancers / Urinary Tract Cancers1
2RecruitingTreatmentCancer, Breast2
2RecruitingTreatmentCancer, Breast / HER-2 Positive Breast Cancer / Stage II Breast Cancer / Stage III Breast Cancer1
2RecruitingTreatmentCancer, Breast / Neoplasms Metastasis1
2RecruitingTreatmentCancer, Breast / Neoplasms, Breast / Tumors, Breast1
2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2RecruitingTreatmentMetastatic Colorectal Cancers1
2WithdrawnTreatmentCancer, Breast1
2, 3CompletedTreatmentMalignant Neoplasm of Stomach1
2, 3RecruitingTreatmentEarly-Stage Breast Carcinoma / HER-2 Positive Breast Cancer1
3Active Not RecruitingTreatmentCancer, Breast4
3CompletedTreatmentCancer, Breast3
3CompletedTreatmentCancer, Breast / Neoplasms, Breast1
3CompletedTreatmentMetastatic Breast Cancer (MBC)1
3RecruitingTreatmentCancer, Breast1
4RecruitingBasic ScienceHER2 Positive Breast Cancer, Metastatic Breast Cancer, Locally Advanced Breast Cancer1
Not AvailableActive Not RecruitingDiagnosticBone Metastases / Hepatic Metastases / Her2-Positive Breast Cancer / Lung Cancer Metastatic / Recurrent Breast Cancer / Soft Tissue Metastases / Stage IV Breast Cancer1
Not AvailableNo Longer AvailableNot AvailableMetastatic Breast Cancer (MBC)1
Not AvailableRecruitingNot AvailableCancer, Breast / Pregnancy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous20 mg/1mL
Powder, for solutionIntravenous100 mg
Powder, for solutionIntravenous160 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

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

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
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. Barginear MF, John V, Budman DR: Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer. Mol Med. 2013 Jan 22;18:1473-9. doi: 10.2119/molmed.2012.00302. [PubMed:23196784]
  2. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RV, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX: Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008 Nov 15;68(22):9280-90. doi: 10.1158/0008-5472.CAN-08-1776. [PubMed:19010901]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Kuper JI, D'Aprile M: Drug-Drug interactions of clinical significance in the treatment of patients with Mycobacterium avium complex disease. Clin Pharmacokinet. 2000 Sep;39(3):203-14. [PubMed:11020135]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Authors unspecified: Trastuzumab emtansine. An inadequately assessed combination of two cytotoxic drugs. Prescrire Int. 2014 Dec;23(155):289. [PubMed:25629144]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on November 18, 2007 11:27 / Updated on December 14, 2018 05:39