Introduction of Ganitumab

Ganitumab (AMG 479) is a fully human monoclonal antibody (IgG1) isolated against the human insulin-like growth factor receptor type I (IGF-IR). Ganitumab, now developed by the immuno-oncology start-up company NantCell (a subsidiary of NantWorks), was first produced by Amgen as a pancreatic cancer drug candidate. However, in 2012, the company terminated the late stage pancreatic cancer trial of ganitumab because it showed no significant improvement in patients’ survival. Recently, ganitumab was designated by Food and Drug Administration (FDA) as an orphan drug designation to treat Ewing’s sarcoma. So far it hasn't passed FDA Approved for Orphan Indication, and the phase 3 clinical trial (NCT02306161) is ongoing. In addition to Ewing sarcoma, ganitumab also is being investigated for the treatment of rhabdomyosarcoma, advanced solid tumors, and breast cancer when used in combination with other medicines.

Mechanism of Action of Ganitumab

The insulin family of growth factors is an evolutionally conserved system which plays a crucial role in the growth and development of many tissues and the regulation of overall growth and metabolism. This system comprises three receptors [insulin receptor (IR), IGF-1 receptor (IGF-1R), and IGF-2/mannose 6-phosphate receptor (M-6-PR)], three ligands (insulin, IGF-1, and IGF-2), and six known types of circulating IGF-binding proteins (IGFBP1-6). The IGF-1R is highly homologous to the IR.

The IGF-1R is a receptor tyrosine kinase with a structure of a heterotetrameric glycoprotein composed of two α and two β subunits, post-transcriptionally linked by disulfide bonds, which regulates cell survival and cell cycle progression via the PI3K/Akt and extracellular signal regulated kinase pathways through insulin receptor substrate-1to-4 (IRS-1to-4) and Src-homology collagen (Shc) adapter proteins. Phosphorylation of the IRS adapter molecules on one hand triggers activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, whereas, on the other hand, the Shc adapter activates signaling by the Ras/Raf/MEK/Erk signaling pathway. IGF-IR seems to be expressed in most human cancers. The two IGF-1R ligands, IGF-1 and IGF-2, have been implicated in cancer initiation and progression.

In the past decades, a large amount of evidence has emphasized that IGF-IR play a key role in the transformation of cells, cancer cell proliferation, as well as in metastatic events, associated in various types of human cancers. It seems that inhibition of IGF-IR signaling can generate antineoplastic effects. A number of monoclonal antibodies have been developed to target the receptor itself, which bind to the extracellular domains of the IGF-1R and block ligand binding. A feature common to all anti-IGF-1R antibodies, probably more important than the blocking activity itself, is their ability to down-regulate of the IGF-1R overtime by promoting internalization of the receptor. Receptor targeting antibodies might have important therapeutic advantages, concerning both specificity and toxicity. A variety of fully human anti-IGF-1R monoclonal antibodies have been characterized and showed strong anti-tumor activity in vitro and in vivo.

Ganitumab is one of the fully human monoclonal antibodies against the IGF-1R, and displays the following roles: (a) inhibit binding of IGF-1 and IGF-2 to IGF-1R; (b) block the activation of IGF-1R homodimers and IGF-1R/IR hybrid receptors, but not IR homodimers; (c) promote down-regulation of IGF-1R, thus inhibiting tumor cell proliferation and induces the death of tumor cells.

Figure 1 Mechanism of Action of Ganitumab

Clinical Projects of Ganitumab *

What We Provide

* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?term=Ganitumab&Search=Apply&recrs=b&recrs=a&recrs=f&recrs=d&age_v=&gndr=&type=&rslt=

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