Nimotuzumab

Nimotuzumab binds to the extracellular domain of epidermal growth factor receptor (EGFR, HER1, c-ErB1) and inhibits the binding of epidermal growth factor (EGF) and other ligands such as transforming growth factor alfa. The intrinsic properties of nimotuzumab require bivalent binding (i.e., binding with both antibody arms to two targets simultaneously) for stable attachment to cellular surface, which leads to nimotuzumab selectively binding to cells that express moderate to high EGFR levels.

The EGFR is a transmembrane glycoprotein that is a member of a family of receptors named HER. EGFR is expressed in cells from all three embryonic layer cells, especially in cells of epithelial origin (Skin, respiratory tract, gastrointestinal tract, urinary tract and liver). In wide diversity of human tumors of epithelial origin like head and neck (SCCHN), non small cell lung cancer (NSCLC), pancreatic, colon, breast, kidney ovarian and bladder carcinomas EGFR is over expressed. It is also over expressed in gliomas.

Binding of Nimotuzumab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased vascular endothelial growth factor production.

In vitro studies using tumor cell lines like A431, MDA-MB-435, U87 and in vivo studies in human tumor xenografted SCID mice have shown that nimotuzumab has anti-proliferative, anti-angiogenic and proapoptotic activity.

Nimotuzumab administered in combination with concomitant chemotherapy or radiotherapy exhibits nonlinear pharmacokinetics. Following a 30 minute infusion the area under the concentration time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 50 to 400 mg. Nimotuzumab clearance (CL) decreased from 1.08 to 0.34 mL/h/kg as the dose increased from 50 to 200, and at doses >200 mg, it appeared to plateau. The volume of the central compartment (Vc) for Nimotuzumab ranged from 2.3 to 7.2L and the maximal concentration C_max was 27 to 57 ng/mL for the same dose range. The elimination half life (t_1/2ß) ranged from 62.91 to 304.51 hrs for the doses 50 to 400mg.

In the human body, Nimotuzumab is mainly distributed in liver, spleen, heart, kidney and bladder. Liver uptakes most of the Nimotuzumab. Evidence from animal pharmacokinetic study indicates that the concentration of the antibody in tumor is highest at 24 hours after injection.

Immunogenicity

The immunotoxicity studies in green monkeys consisting of four intra-dermal doses of adjuvanted-Nimotuzumab elicited only sub maximal immunogenic response, suggestive of lesser immunogenecity with non adjuvanted Nimotuzumab.

Immunogenicity [human anti-human antibody (HAHA)] to determine the antiidiotypic response against Nimotuzumab was evaluated in clinical studies at single and multiple doses to a maximum of 2400mg with a follow-up of one year. Out of the 34 patients evaluated only one patient showed a response.

The low anti-idiotypic response is indicative of the humanized nature of the antibody and may also be responsible for the low hypersensitivity reaction. The development of an immunogenic response is dependent on a number of factors like timing of sample collection, sample handling, time of collection, underlying disease and concomitant medication. The incidence of development of antibodies to Nimotuzumab is not conclusive.