Trastuzumab Overview

Introduction of Trastuzumab

Trastuzumab is a recombinant IgG1 kappa, humanized monoclonal antibody (mAb) that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor (HER2) protein. It is produced in Chinese hamster ovary (CHO) cell culture. It is sold under the brand name Herceptin among others for the treatment of early stage HER2-positive breast cancer, or metastatic breast cancer that substantially overexpress HER2. It may be used by itself or together with other chemotherapy medication. Trastuzumab is given by slow injection into a vein and injection just under the skin. Trastuzumab was approved for medical use in the United States in 1998. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.

Mechanism of Action of Trastuzumab

The HER (human epidermal growth factor receptor) protein, binds to human epidermal growth factor, and stimulates cell proliferation. In some cancers, notably certain types of breast cancer, HER2 is over-expressed and causes cancer cells to reproduce uncontrollably. HER2 extends across the cell membrane, and carries signals from outside the cell to the inside. Signaling compounds called mitogens (specifically EGF in this case) arrive at the cell membrane, and bind to the extracellular domain of the HER family of receptors. Those bound proteins then link (dimerize), activating the receptor. HER2 sends a signal from its intracellular domain, activating several different biochemical pathways. These include the PI3K/Akt pathway and the MAPK pathway. Signals on these pathways promote cell proliferation and the growth of blood vessels to nourish the tumor (angiogenesis). Because it was recognized that constitutive HER2 signaling can drive breast tumor development and progression, strategies were developed to therapeutically target HER2 activity. The first successful approach began with the development of a mouse mAb called 4D5, which targets an extracellular epitope of the HER2 protein. HER2-specific monoclonal antibody 4D5 blocked phosphorylation of HER2 and suppressed growth of HER2-positive breast cancer cell lines and xenografts. In order to translate 4D5 clinically, a derivative that includes the antigen binding loops of 4D5 and the human variable region and immunoglobulin G1 constant domains was constructed. The recombinant humanized anti-HER2 antibody that resulted from this effort is called trastuzumab. Trastuzumab achieved significant regression of human HER2-overexpressing tumor xenografts as monotherapy or in combination with cytotoxic chemotherapeutic agents. The mechanisms underlying the anticancer activity of trastuzumab are not completely known, but several have been proposed. Some studies have suggested that trastuzumab downregulates total levels of HER2 on the cell surface, which may ultimately reduce downstream PI3K and MAPK signaling. Trastuzumab has been shown to block cleavage of the extracellular domain of HER2, thus, preventing formation of the constitutively active membrane-bound 95-kiloDalton HER2 protein called p95 HER2. Trastuzumab may also selectively inhibit HER2-HER3 heterodimerization, reducing PI3K signaling. Induction of cell cycle arrest by trastuzumab is mediated by p27kip1 and inhibition of cdk2 activity. Furthermore, trastuzumab appears to reduce angiogenesis, which may result in increased permeability of blood vessels, potentially increasing delivery of drugs to the tumor. Finally, HER2-positive cells that become “coated” in trastuzumab will be recognized by specific immune cells, causing antibody-dependent cellular cytotoxicity (ADCC), or lysis of the antibody-bound cells.

Fig.1 Mechanism of action of Trastuzumab

Table 1. Clinical Projects of Trastuzumab*

Table 2. Approved Drugs of Trastuzumab**

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Herceptin	HER2-Overexpressing Breast Cancer, HER2-Overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma	Powder for solution	150 mg / 420 mg	Intravenous infusion	Genentech	September 25, 1998
Ontruzant	Stomach Neoplasms, Breast Neoplasms	Powder for solution	150 mg	Intravenous infusion	Samsung Bioepis UK Limited (SBUK)	November 15, 2017
Herzuma	Stomach Neoplasms, Breast Neoplasms	Powder for solution	150 mg	Intravenous infusion	Celltrion Healthcare Hungary Kft.	February 9, 2018
Kanjinti	Stomach Neoplasms, Breast Neoplasms	Powder for solution	150 mg	Intravenous infusion	Amgen Europe B.V., Breda	May 16, 2018
Herceptin	Stomach Neoplasms, Breast Neoplasms	Powder for solution	150 mg	Intravenous infusion	Roche Registration GmbH	August 28, 2000
Trazimera	Stomach Neoplasms, Breast Neoplasms	Powder for solution	150 mg	Intravenous infusion	Pfizer Europe MA EEIG	July 26, 2018
Herceptin	HER2-Overexpressing Breast Cancer, HER2-Overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma	Powder for solution	440 mg	Subcutaneous	Hoffmann-La Roche Limited	August 23, 1999
Herceptin SC	HER2-Overexpressing Breast Cancer, HER2-Overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma	Concentrate for solution	120 mg / mL	Intravenous infusion	Hoffmann-La Roche Limited	September 11, 2018
Herceptin	HER2-Overexpressing Breast Cancer, HER2-Overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma	Powder for solution	60 mg 150 mg	Intravenous infusion	Chugai Pharmaceutical Co., Ltd	April 4, 2001
Herceptin	HER2-overexpressing Breast Cancer, HER2-overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma	Powder for solution	150 mg	Intravenous infusion	Roche Products Pty Ltd	September 14, 2000
Herclon	HER2-positive Early Breast Cancer, Locally Advanced Breast Cancer, Metastatic Breast Cancer, Advanced Gastric Cancer	Powder for solution	150 mg	Intravenous infusion	Roche Products Pty Ltd	September 15, 2017
Simabtra	HER2-positive Early Breast Cancer, Locally Advanced Breast Cancer, Metastatic Breast Cancer, Advanced Gastric Cancer	Powder for solution	150 mg	Intravenous infusion	Celltrion Healthcare Australia Pty Ltd	July 17, 2018

What We Provide

Therapeutic Antibody

Trastuzumab

We provide high-quality Trastuzumab 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=Trastuzumab

** 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=103792
https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=64277
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=73229
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=289147
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=291750
https://www.ema.europa.eu/medicines/human/EPAR/kanjinti
https://www.ema.europa.eu/medicines/human/EPAR/herzuma
https://www.ema.europa.eu/medicines/human/EPAR/ontruzant
https://www.ema.europa.eu/medicines/human/EPAR/herceptin
https://www.ema.europa.eu/medicines/human/EPAR/trazimera
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4291406D3

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