Pembrolizumab Overview

Introduction of Pembrolizumab

Pembrolizumab (formerly MK-3475 and lambrolizumab, trade name Keytruda) is a humanized monoclonal antibody (mAb) used in cancer immunotherapy. It is an IgG4 isotype antibody that blocks a protective mechanism of cancer cells, and allows the immune system to destroy those cancer cells. It targets the programmed cell death 1 (PD-1) receptor of lymphocytes. Pembrolizumab was invented by scientists Gregory Carven, Hans van Eenennaam and John Dulos at Organon after which they worked with Medical Research Council Technology (now known as LifeArc) starting in 2006 to humanize the antibody; Schering-Plough acquired Organon in 2007 and Merck & Co. acquired Schering-Plough two years later. On September 4, 2014, the US Food and Drug Administration (FDA) approved pembrolizumab under the FDA Fast Track Development Program. It is approved for use following treatment with ipilimumab, or after treatment with Ipilimumab and a BRAF inhibitor in advanced melanoma patients who carry a BRAF mutation. In July 2015, pembrolizumab received marketing approval in Europe. By April 2016, Merck applied for approval to market the drug in Japan and signed an agreement with Taiho Pharmaceutical to co-promote it there.  On October 2, 2015, the FDA approved pembrolizumab for the treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors express PD-L1 and who have failed treatment with other chemotherapeutic agents. In May 2017, pembrolizumab received an accelerated approval from the FDA for use in any unresectable or metastatic solid tumor with DNA mismatch repair deficiencies or a microsatellite instability-high state (or, in the case of colon cancer, tumors that have progressed following chemotherapy). This approval marked the first instance in which the FDA approved marketing of a drug based only on the presence of a genetic mutation, with no limitation on the site of the cancer or the kind of tissue in which it originated. In June 2018, the FDA approved pembrolizumab for use in both advanced cervical cancer for PD-L1 positive patients and for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after two or more prior lines of therapy.

Mechanism of Action of Pembrolizumab

PD-1 is the transmembrane programmed cell death 1 protein (also called PDCD1 and CD279). As an immune checkpoint molecular, it interacts with PD-L1 (PD-1 ligand 1, or CD274). PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities. The PD-1 checkpoints function as a control over immune response hyperactivity. However, these immune checkpoints are also means by which tumors can inhibit T cells and block antitumor immune response. Interaction between PD-1 and PD-L1 and PD-L2 normally inhibits immune response by reducing T lymphocyte function. Signaling inhibits T cell activation, proliferation, and cytokine production. Regulation of T cell activation involves two complementary signals: TCR recognition of peptide/MHC and costimulatory signal provided by CD28 ligation to B7.1 or B7.2 on APCs. Many tumors express PD-L1 in order to induce negative regulation of T cells by the PD-1 checkpoint. Pembrolizumab inhibits checkpoint binding of PD-1 and PD-L1 between T cells and the tumor cells, thus inducing immune response.

Fig.1 Mechanism of action of pembrolizumab

Table 1. Clinical Projects of Pembrolizumab*

Table 2. Approved Drugs of Pembrolizumab**

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Keytruda	Melanoma, Non-Small Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Cancer (HNSCC), Classical Hodgkin Lymphoma (cHL), Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Urothelial Carcinoma, Microsatellite Instability-High Cancer, Gastric Cancer, Cervical Cancer	Powder for solution	50 mg	Intravenous infusion	Merck Sharp & Dohme	September 4, 2014
Keytruda	Melanoma; Hodgkin Disease; Carcinoma, Non-Small-Cell Lung	Powder for solution	50 mg	Intravenous infusion	Merck Sharp & Dohme B.V.	July 17, 2015
Keytruda	Melanoma, Non-Small Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Cancer (HNSCC), Classical Hodgkin Lymphoma (cHL), Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Urothelial Carcinoma, Microsatellite Instability-High Cancer, Gastric Cancer, Cervical Cancer	Powder for solution	50 mg	Intravenous infusion	Merck Canada Inc	June 1, 2015
Keytruda	Melanoma, Non-Small Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Cancer (HNSCC), Classical Hodgkin Lymphoma (cHL), Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Urothelial Carcinoma, Microsatellite Instability-High Cancer, Gastric Cancer, Cervical Cancer	Powder for solution	50 mg	Intravenous infusion	Merck Sharp & Dohme (Australia) Pty Ltd	August 3, 2016
Keytruda	Melanoma, Non-Small Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Cancer (HNSCC), Classical Hodgkin Lymphoma (cHL), Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Urothelial Carcinoma, Microsatellite Instability-High Cancer, Gastric Cancer, Cervical Cancer	Powder for solution	50 mg	Intravenous infusion	MSD K.K.	September 28, 2016

What We Provide

Therapeutic Antibody

Pembrolizumab

We provide high-quality Pembrolizumab 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=Pembrolizumab

** Information presented in the table were collected from the following websites:
https://www.ema.europa.eu/medicines/human/EPAR/keytruda
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo= 125514
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=263932 https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=92551
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4291435A1

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