Ado-trastuzumab Emtansine Overview

Introduction of Ado-trastuzumab Emtansine

Ado-trastuzumab emtansine, sold under the trade name Kadcyla, is an antibody-drug conjugate (ADC) consisting of the monoclonal antibody (mAb) trastuzumab (trade name Herceptin) linked to the cytotoxic agent emtansine (DM1). It was developed by Genentech, a subsidiary group of Roche, and is manufactured by Lonza. In the United States, Kadcyla was approved with the generic name "ado-trastuzumab emtansine", rather than the original United States Adopted Name (USAN) issued in 2009, "trastuzumab emtansine". The "ado-" prefix was added to help prevent dispensing errors. During preclinical development and clinical trials, the drug was also known as trastuzumab-DM1 or trastuzumab-MCC-DM1 (after the codename for emtansine), both abbreviated T-DM1, and by the codename PRO132365. Ado-trastuzumab emtansine was approved in the United States specifically for treatment of HER2-positive metastatic breast cancer (mBC) in patients who have been treated previously with trastuzumab and a taxane (paclitaxel or docetaxel), and who have already been treated for mBC or developed tumor recurrence within six months of adjuvant therapy. Approval was based on the EMILIA study, a phase III clinical trial that compared trastuzumab emtansine versus capecitabine (Xeloda) plus lapatinib (Tykerb) in 991 people with unresectable, locally advanced or metastatic HER2-positive breast cancer who had previously been treated with trastuzumab and taxane chemotherapy. This trial showed improved progression-free survival in patients treated with trastuzumab emtansine (median 9.6 vs. 6.4 months), along with improved overall survival (median 30.9 vs. 25.1 months) and safety.

Mechanism of Action of Ado-trastuzumab Emtansine

Ado-trastuzumab emtansine is an ideal ADC that combines the best components: specific monoclonal antibody trastuzumab, potent cytotoxic agent DM1, and stable thioether linker. Trastuzumab, a monoclonal antibody targeted to the HER2 receptor, is widely utilized for the treatment of patients with HER2-positive early stage, locally advanced and metastatic breast cancer. This agent causes cell death through antibody-mediated cellular cytotoxicity (ADCC), HER2 downregulation, as well as other proposed mechanisms, and has revolutionized the treatment of HER2-positive breast cancers. DM1 maytansinoid, derivative of maytansine, is the highly potent cytotoxic in trastuzumab emtansine. DM1 is an antimitotic agent that inhibits microtubule assembly leading to cell cycle arrest and apoptosis. This agent is effective at picomolar concentrations. Although DM1 interact with the microtubules as the vinca alkaloid, it is 20-100 times more potent than vincristine. DM1 is also 24-270 times more potent than agents used in conventional chemotherapy, such as paclitaxel. The linker is a nonreducible thioether bond ([N-maleimidomethyl]cyclohexane-1-carboxylate) MCC that binds trastuzumab to DM1. The ideal linker should be stable in circulation to minimize the risk of systemic toxicities. However, the linker should efficiently release the cytotoxic agent upon ADC internalization. After binding to the HER2 receptor, the HER2 receptor and drug-antibody conjugate are internalized via endocytosis. Intracellularly, DM1 is separated from the antibody by lysosomal degradation and binds to tubulin. This disrupts the microtubules causing cell cycle arrest and apoptosis. While trastuzumab is utilized to deliver emtansine to the cell, it also retains its properties of ADCC, inhibition of HER2 signaling pathways, and prevention of HER2 receptor shedding.

Fig.1 Mechanism of action of ado-trastuzumab emtansine

Table 1. Clinical Projects of Ado-trastuzumab Emtansine*

NCT ID

Status

Conditions

Lead Sponsor

Update Time

NCT02675829	Recruiting	Solid Tumor Cancers, Lung Cancer, Bladder Cancer, Urinary Tract Cancers	Memorial Sloan Kettering Cancer Center	February 5, 2016
NCT01983501	Active, not recruiting	HER2 Positive Breast Cancers	Cascadian Therapeutics Inc.	November 14, 2013
NCT02226276	Active, not recruiting	Bone Metastases, HER2-positive Breast Cancer, Liver Metastases, Lung Metastases, Recurrent Breast Cancer, Soft Tissue Metastases, Stage IV Breast Cancer	City of Hope Medical Center	August 27, 2014
NCT02414646	Active, not recruiting	Estrogen Receptor Status, HER2 Positive Breast Carcinoma, Progesterone Receptor Status, Stage I Breast Cancer AJCC v7, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7	Academic and Community Cancer Research United	April 13, 2015
NCT03429101	Recruiting	Breast Cancer	Spectrum Pharmaceuticals, Inc	February 12, 2018
NCT03190967	Recruiting	Breast Cancer, Brain Metastasis, Brain Cancer	National Cancer Institute (NCI)	June 19, 2017
NCT03529110	Recruiting	Breast Cancer	Daiichi Sankyo, Inc.	May 18, 2018
NCT00833963	Recruiting	Breast Cancer, Pregnancy	Genentech, Inc.	February 2, 2009
NCT03587740	Recruiting	Breast Cancer	Dana-Farber Cancer Institute	July 16, 2018
NCT03530696	Not yet recruiting	HER2-positive Breast Cancer, Breast Cancer, Breast Cancer Stage, Recurrent Breast Cancer, Metastatic Breast Cancer, HER2 Positive Breast Carcinoma	University of Arizona	May 21, 2018
NCT03025711	Recruiting	Breast Neoplasms	BELEN RUIZ-ANTORAN	January 19, 2017
NCT02236000	Recruiting	Breast Cancer	NSABP Foundation Inc	September 10, 2014
NCT03203616	Not yet recruiting	Metastatic HER2-positive Breast Cancer With Brain Metastasis	Jules Bordet Institute	June 29, 2017
NCT02305641	Recruiting	Breast Cancer	Hoffmann-La Roche	December 2, 2014
NCT02326974	Recruiting	HER-2 Positive Breast Cancer, Breast Cancer, Stage II Breast Cancer, Stage III Breast Cancer	Dana-Farber Cancer Institute	December 30, 2014
NCT02073916	Active, not recruiting	Metastatic Breast Cancer	Jenny C. Chang, MD	February 27, 2014
NCT01853748	Active, not recruiting	Breast Cancer	Dana-Farber Cancer Institute	May 15, 2013
NCT02562378	Recruiting	Breast Cancer	MedSIR	September 29, 2015
NCT03032107	Recruiting	Breast Cancer	Dana-Farber Cancer Institute	January 26, 2017
NCT02658084	Active, not recruiting	Breast Cancer, Metastatic Breast Cancer	University of Miami	January 18, 2016
NCT01835236	Active, not recruiting	Metastatic Breast Cancer	Swiss Group for Clinical Cancer Research	April 18, 2013
NCT02038010	Active, not recruiting	HER2-positive Breast Cancer, Recurrent Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer	Northwestern University	January 16, 2014
NCT01976169	Recruiting	Advanced Breast Cancer	University of Texas Southwestern Medical Center	November 5, 2013
NCT03153163	Active, not recruiting	Breast Neoplasms	Hoffmann-La Roche	May 15, 2017
NCT02657343	Recruiting	Breast Cancer	Dana-Farber Cancer Institute	January 15, 2016
NCT03084939	Recruiting	Breast Cancer	Hoffmann-La Roche	March 21, 2017
NCT03418558	Recruiting	Metastatic Colorectal Cancer	Fondazione del Piemonte per l'Oncologia	February 1, 2018
NCT03225937	Recruiting	Metastatic Colorectal Cancer	Fondazione del Piemonte per l'Oncologia	July 21, 2017
NCT02658734	Recruiting	HER3 Positive Breast Cancer, Metastatic Breast Cancer, Locally Advanced Breast Cancer	Hoffmann-La Roche	January 20, 2016
NCT01702571	Active, not recruiting	Breast Cancer	Hoffmann-La Roche	October 8, 2012
NCT01597414	Active, not recruiting	Elderly Metastatic Breast Cancer Population	European Organisation for Research and Treatment of Cancer - EORTC	May 14, 2012
NCT01772472	Active, not recruiting	Breast Cancer	Hoffmann-La Roche	January 21, 2013
NCT01966471	Active, not recruiting	Breast Cancer	Hoffmann-La Roche	October 21, 2013
NCT02924883	Active, not recruiting	Metastatic Breast Cancer	Hoffmann-La Roche	October 5, 2016
NCT01745965	Active, not recruiting	Breast Cancer	West German Study Group	December 10, 2012
NCT00781612	Recruiting	Neoplasm Metastasis	Genentech, Inc.	October 29, 2008
NCT03248492	Active, not recruiting	Breast Cancer	Daiichi Sankyo, Inc.	August 14, 2017
NCT03364348	Recruiting	HER2 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 Cancer	George W. Sledge Jr.	December 6, 2017
NCT01565200	Active, not recruiting	HER-2 Positive Breast Cancer	Jules Bordet Institute	March 28, 2012
NCT03709082	Recruiting	HER2-positive Breast Cancer, Breast Cancer Metastatic	University of Kansas Medical Center	October 17, 2018
NCT03523585	Recruiting	Breast Cancer	Daiichi Sankyo, Inc.	May 14, 2018
NCT02073487	Active, not recruiting	Breast Cancer	Jenny C. Chang, MD	February 27, 2014
NCT02605915	Active, not recruiting	HER2-Positive Metastatic Breast Cancer, HER2-Negative Metastatic Breast Cancer, Locally Advanced or Early Breast Cancer	Hoffmann-La Roche	November 16, 2015
NCT02314481	Recruiting	Non-small Cell Lung Cancer	University College, London	December 11, 2014

Table 2. Approved Drugs of Ado-trastuzumab Emtansine**

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Kadcyla	HER2-positive, Metastatic Breast	Powder for solution	100 mg / 160 mg	Intravenous infusion	Genentech	February 22, 2013
Kadcyla	Breast Neoplasms	Powder for solution	100 mg / 160 mg	Intravenous infusion	Roche Registration GmbH	November 15, 2013
Kadcyla	HER2-positive, Metastatic Breast	Powder for solution	100 mg / 160 mg	Intravenous infusion	Hoffmann-La Roche Limited	October 9, 2013
Kadcyla	HER2-positive, Metastatic Breast	Powder for solution	100 mg / 160 mg	Intravenous infusion	Roche Products Pty Ltd	September 3, 2013
Kadcyla	HER2-positive, Metastatic Breast	Powder for solution	100 mg / 160 mg	Intravenous infusion	Chugai Pharmaceutical Co., Ltd	September 20, 2013

What We Provide

Therapeutic Antibody

Trastuzumab Emtansine

We provide high-quality Trastuzumab Emtansine for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

Reference
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Ado-trastuzumab+Emtansine

** Information presented in the table were collected from the following websites:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125427
https://www.ema.europa.eu/medicines/human/EPAR/kadcyla
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=201622
https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=89698
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4291426D1

For research use only. Not intended for any clinical use.