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.
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||Solution for infusion||10 mg / mL||Intravenous s injection||Eli Lilly Japan K.K.||June 20, 2016|
* The table was excerpted from the following website
** Information presented in the table were collected from the following website: