Country of origin:
First introduction: Introduced by:
Trade name: CAS registry no:
Center for Molecular Immunology India
YM Biosciences Biocon
Pharmaceuticals BioMab EFGR, Theraloc 828933-51-3
Molecular weight: Expression System: Manufacturer:
Humanized murine IgG2a monoclonal antibody R3 EGFR antagonist
~150kDa NSO cells
Overexpression of epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase, is prevalent in malignant tumors of epithelial origin and is especially common in breast, head and neck, colon, and lung cancer. With EGFR overexpression, prognosis is poor due to associated tumor invasion, metastasis, enhanced angiogenesis, and resistance to chemotherapy; thus, modulation of EGFR-mediated signaling is an attractive target for intervention. Small-molecule kinase inhibitors (gefitinib and erlotinib) and a monoclonal antibody (cetuximab) specific for EGFR are in clinical evaluation, but treatment cessation due to development of severe acne-like rash is common with these EGFR antagonists. Notably, nimotuzumab, a humanized form of the murine IgG2a monoclonal antibody that has been launched in India for treatment of head and neck cancers overexpressing EGFR, demonstrates clinical efficacy devoid of the rash toxicity. Presumably, humanization of the antibody sequence eliminates hypersensitivity reactions and human anti-mouse antibody (HAMA) responses, as well as, improves pharmacokinetic and effector functions in patients. While beyond the scope of this review, a technetium-labeled (99mTc) nimotuzumab has been developed for diagnostic purposes while its 188Re-labeled counterpart emits p-particles for targeted radioimmunotherapy. The pharmacokinetic parameters and tissue localization, however, were determined with [99mTc]nimotuzumab. Following a 27mCi dose (3 or 6mg i.v.), the radiopharmaceutical was cleared rapidly from the blood with a normal tissue distribution half-life of 10.8 +3.8 min.The volume of distribution and clearance were 180 + 37mL/kg and 14 + 37mL/kg/min, respectively. The liver, spleen, and kidneys demonstrated the largest radioactivity uptake, and it was determined that 19-24% of the agent was excreted in the urine. From repeated weekly intravenous dosing of nimotuzumab to patients with squamous cell carcinoma of the head and neck (SCCHN), the minimum and maximum steady-state concentrations increased linearly with dose. For the 200-mg dose, the range was 19-76 mg/mL compared to 39-147 mg/mL for the 400-p.g dose. Nimotuzumab is prepared by genetic engineering of the murine IgG2a monoclonal antibody R3, secreted by hybridoma obtained from the fusion of murine myeloma cells with splenocytes from BALB/c mice immunized with partially purified human placental EGFR. The humanized h-R3 IgG1 antibody (nimotuzumab) is obtained by grafting the complementarity-determining regions of R3 onto the human frameworks, the light and heavy chains of REI and EU chosen for their high homology with the corresponding sequences of R3. Since this original approach led to a dramatic reduction in the binding of the antibody, evaluation of selective mutation back to a few original murine amino acids concluded that Ser75, Thr76, and Thr93 should be retained. By interacting with one epitope in the extracellular domain of EGFR, nimotuzumab blocks ligand binding and subsequent EGF-dependent receptor phosphorylation. In addition, nimotuzumab displays a similar affinity to that of EGF (~1 nM). The efficacy of nimotuzumab was evaluated in patients with advanced (unresectable) SCCHN with demonstrable overexpression of EGFR. For a duration of 6 weeks in combination with radiotherapy (60-66 Gy in 30 fractions), a total of 24 patients were administered weekly intravenous infusions of nimotuzumab (50, 100, 200, or 400 mg). Seven patients demonstrated a partial or complete response while one patient receiving the 200-mg dose was disease-free after resection of the residual tumor. The overall survival was significantly increased at the two higher doses (median of 44.3 months) compared to the lower doses (median of 8.6 months). Furthermore, three-year survival was superior (66.7%) in patients receiving the higher doses of 200 or 400 mg compared with the survival rate for patients at the lower doses (16.7%). These results were confirmed by a parallel study in Canada where 70% of SCCHN patients achieved complete responses after doses of 100 mg and 200 mg of nimotuzumab in combination with radiation therapy. Equivalent response rates to those achieved with chemoradiation were observed without the toxicities associated with chemotherapy. The adverse events associated with nimotuzumab treatment included mild-to-moderate fever, hypotension, hypertension, vomiting, nausea, dry mouth, and tremors; however, no anaphylactic or skin reactions, prevalent with anti-EGFR agents, were observed.
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