Necitumumab Overview

Introduction of Necitumumab

Necitumumab (IMC-11F8, LY3012211) is a second-generation fully human immunoglobulin (Ig) G1 kappa isotype monoclonal antibody (mAb) that acts as an antagonist to direct against the extracellular region of epidermal growth factor receptor (EGFR). It was developed by Eli Lilly & Co (Indianapolis, IN, USA) and produced in genetically engineered mammalian NS0 cells. It was first approved by the U.S. Food and Drug Administration (FDA) under the brand name Portrazza in 2015, for use in combination with cisplatin and gemcitabine as a first-line treatment for metastatic squamous non-small cell lung cancer (NSCLC). After that, it has gained the approval for marketing in the Europe Union and Japan respectively in 2016 and 2017. It is not indicated for treatment of non-squamous NSCLC. Currently, there are several ongoing clinical trials investigating necitumumab in the treatment of NSCLC in several different settings. It is currently being studied in combination with pre-existing agents, such as osimertinib, pembrolizumab, nabpaclitaxel, and carboplatin, as well as with new agents under investigation, abemaciclib and AZD9291. Necitumumab is currently being evaluated in the second-line setting following treatment failure or progression with front-line EGFR tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy.

Mechanism of Action of Necitumumab

Under normal conditions, the extracellular interaction between EGFR and its ligand, the epidermal growth factor (EGF), leads to dimerization of the receptor, binding with adenosine triphosphate (ATP) in the intracellular region of the receptor, and the activation of downstream signaling pathways that involve a number of subsequent protein-based cascades, such as the Kirsten rat sarcoma (RAS) - rapidly accelerated fibrosarcoma (RAF) - mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3-kinase (PI3K) - protein kinase B (PKB, also known as Akt) - mammalian target of rapamycin complex (mTORc) pathway; these signaling cascades ultimately lead to the promotion of cell proliferation and survival. While this process has a physiologic role in the development of tissues and organs, it is also a key player in the growth of several types of neoplasms, including lung cancer. Necitumumab contains an antigen-binding fragment, known as FAB-11F8, with high affinity for one of the ligand-binding extracellular domains of EGFR; as a consequence of competitive binding, the mAb prevents the dimerization of EGFR and the subsequent signaling cascade, resulting in internalization and degradation of the receptor, ultimately followed by inhibition of proliferation and survival. Additionally, since necitumumab belongs to the IgG1 class, it retains the ability to induce antibody-dependent cell cytotoxicity (ADCC) by stimulating response from adaptive immune cells (such as lymphocytes), which exert their activity on opsonized neoplastic cells (e.g. activating the perforin/granzymes mechanism), resulting in immune-mediated cell lysis.

Fig.1 Mechanism of action of necitumumab

Clinical Projects of Necitumumab*

Approved Drugs of Necitumumab**

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Portrazza	Metastatic squamous non-small cell lung cancer	Injection, solution	16 mg/mL	Intravenous	Eli Lilly Co.	November 24, 2015
Portrazza	Carcinoma, Non-Small-Cell Lung	Injection, solution	16 mg/mL	Intravenous	Eli Lilly Nederland B.V.	February 15, 2016
Portrazza	Squamous Non-Small Cell Lung Cancer	Injection, solution	16 mg/mL	Intravenous	Eli Lilly Canada Inc.	March 16, 2017

What We Provide

Therapeutic Antibody

Necitumumab

We provide high-quality Necitumumab 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.

Resources
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Necitumumab

** Information presented in the table were collected from the following websites:
https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=95022
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo= 125547
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003886/human_med_001953.jsp

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