Ramucirumab Overview

Introduction of Ramucirumab

Ramucirumab (LY3009806, IMC-1121B, trade name Cyramza), a fully human monoclonal antibody (mAb) selectively targeted against vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2), has received Food and Drug Administration (FDA) approval for several malignancies. Ramucirumab was developed by ImClone Systems Inc. (now a part of Eli Lilly and Company) and was isolated from a native phage display library from Dyax. It is indicated for treatment of (1) advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma as a single agent or in combination with paclitaxel after fluoropyrimidine-containing or platinum-containing chemotherapy, (2) metastatic colorectal cancer in combination with irinotecan, fluorouracil, and leucovorin (FOLFIRI) after disease progression on or after previous therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine, and (3) metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel after disease progression with or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase mutations should have also experienced treatment failure with an FDA-approved targeted therapy before treatment with ramucirumab for NSCLC. Due to its mechanism of action, ramucirumab has the potential for activity in many malignancies and is being evaluated in clinical trials for additional indications.

Mechanism of Action of Ramucirumab

Angiogenesis, which means the formation of new blood vessels, is an important mechanism for the transport of essential nutrients, oxygenated blood, growth factors, hormones, and proteolytic enzymes to the cells. Angiogenesis affects the hemostasis by controlling the coagulation pathway and is also involved metastases of tumor cells. VEGF and VEGF-receptors (VEGFRs) play a vital role in both physiological and pathological angiogenesis. Multiple signaling pathways were triggered by the activation of VEGF/VEGFR axis that results in survival, proliferation, and migration of endothelial cells. Furthermore, VEGF is also associated with vessel permeability, causing malignant effusions. However, VEGF over-expression has been associated with worsening progression of the tumors and prognosis in several kinds of solid carcinomas. The mechanism of angiogenesis involves various VEGF ligands like VEGF-A to-E, placental growth factor and VEGFRs like VEGFR-1, -2, and -3, which are present on the surface of endothelial cells. VEGF-A is the main ligand, which is associated with neo-angiogenesis, lymphangiogenesis, and tumor permeability. VEGFR-1 and VEGFR-2 are the tyrosine kinase receptors for the ligand VEGF-A. VEGFR-2 involved in neo-angiogenesis, endothelial intracellular signaling, and lymphangiogenesis is associated with stronger signal transmission and is responsible for most of the actions of VEGF-A. VEGFR-2 is also frequently over-expressed in tumor vasculature than normal vasculature and is responsible for tumor spread. Inhibition of tumor growth and spread is noticed by blocking the VEGFR-2 signaling pathway by antibodies directed against either VEGF-A or VEGFR-2 and VEGFR-2 tyrosine kinase inhibitors. Various anti-VEGF antibodies are used in clinical practice, only few drugs have been evaluated which directly and specifically inhibits VEGFR-2. Ramucirumab has strong affinity to the extracellular domain of VEGFR-2 and thus binds there. Unlike all other angiogenic inhibitors, the anti-angiogenic activity of this fully human monoclonal antibody is because of its exclusive binding to human VEGFR-2, which is the main receptor involved in angiogenesis. Inhibition of this receptor activation impedes VEGF-A mediated neo-angiogenesis, which ultimately results in reduced tumor vascularity and growth.

Fig.1 Mechanism of Action of Ramucirumab

Table 1. Clinical Projects of Ramucirumab*

Table 2. Approved Drugs of Ramucirumab**

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Cyramza	Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma, non-small cell lung cancer, metastatic colorectal cancer	Solution for infusion	10 mg / mL	Intravenous s injection	ELI LILLY AND CO	April 21, 2014
Cyramza	Stomach Neoplasms	Solution for infusion	10 mg / mL	Intravenous s injection	Eli Lilly Nederland B.V.	December 19, 2014
Cyramza	Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma, non-small cell lung cancer, metastatic colorectal cancer	Solution for infusion	10 mg / mL	Intravenous s injection	Eli Lilly Canada Inc	September 10, 2015
Cyramza	Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma, non-small cell lung cancer, metastatic colorectal cancer	Solution for infusion	10 mg / mL	Intravenous s injection	Eli Lilly Australia Pty Ltd Pty Ltd	July 23, 2015
Cyramza	Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma, non-small cell lung cancer, metastatic colorectal cancer	Solution for infusion	10 mg / mL	Intravenous s injection	Eli Lilly Japan K.K.	June 20, 2016

What We Provide

Therapeutic Antibody

Ramucirumab

We provide high-quality Ramucirumab (IgG1κ type) for use in IF, IP, Neut, FuncS, ELISA, FC, ICC and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

References
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Ramucirumab
** Information presented in the table were collected from the following website:
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=82744
https://www.ema.europa.eu/en/medicines/human/EPAR/cyramza
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125477
https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=92855
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=227352
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4291429

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