Pharmacokinetics And Pharmacodynamics Study Of Anti-IgE Humanized Monoclonal Antibody

Asthma is a cause of substantial mortality and morbidity and has a considerableeconomic impact. Although medications are available to treat these conditions, some focusonly on symptom relief, others are nonspecific in their mechanism of action (and, therefore,produce substantial side effects). An estimated two-thirds of patients with asthma haveallergic asthma and the causal role of immunoglobulin E (IgE) is well established. Whenallergen cross-links specific IgE bound to high-affinity IgE receptors (FcεRI) on thesurface of basophils and mast cells, pro-inflammatory mediators are released that triggerand perpetuate airway symptomatology. Because of IgE's role in the manifestation of theseconditions, there has been interest in developing therapies that specifically target thisimmunoglobulin to treat allergic asthma. Omalizumab (Xolair, Genentech) is arecombinant humanized monoclonal anti-IgE antibody directed at the FcεRI bindingdomain of human IgE, which represents a novel therapeutic approach in the managementof asthma. Omalizumab has been available in more than30countries worldwide, includingUnited States and European Union, since2003. In China, however, omalizumab has notbeen approved for use and the clinical trials of omalizumab are ongoing.CMAB007, a biosimilar of omalizumab, was developed by National EngineeringResearch Center of Antibody Medicine of China. CMAB007has the same amino acidsequence as omalizumab and both mAbs are expressed in Chinese hamster ovary (CHO)cells. The aim of this study was to investigate the in vitro pharmacodynamics (PD) and invivo pharmacokinetics-pharmacodynamics (PK/PD) in healthy Chinese volunteers.Our in vitro assays indicated that CMAB007displayed similar ability as omalizumabto inhibit the binding of IgE to FcεRI-Ig fusion protein and membrane FcεRI. Importantly,CMAB007did not bind to IgE already bound by membrane FcεRI, suggesting that it didnot crosslink IgE receptor complexes on cells to release histamine. A recombinanteukaryotic expression plasmid pcDNA3.1/FcεRIα was successfully constructed andexpressed transiently in COS-1cells and stably in CHO cells. The induced FcεRIα-Fcfusion protein was identified by dot-blot assay with HRP-mouse anti-human IgG. Then, therecombinant protein was purified by affinity chromatography, and detected by SDS-PAGE.With the FcεRIα-Fc fusion protein, a sensitive and specific enzyme-linked immunosorbentassay (ELISA) method was established to detect CMAB007concentration in human serum．Thirty-six healthy Chinese men participated in two open-label, dose-escalation studies:27in a single-dose study (150,300or600mg) and9in a multiple-dose study (150or300mg every4weeks for20weeks). The safety profiles of both studies were generallyunremarkable. No drug-related adverse event was observed. CMAB007exhibited a linearPK profile over the dose range of150–600mg. In the single-dose study, maximumconcentration (Cmax) was reached within6–8d, and Cmax and area underconcentration-time curve (AUC) increased linearly with the dose. The mean terminalhalf-life (T1/2) was~25d, which roughly coincides with the reported half-life of21d forIgG mAbs. In the multiple-dose study, steady-state appeared to have been achieved afterthe third dose. Css-maxand AUCτalso showed dose-linearity. The pharmacokineticparameters of multiple doses are similar to the single dose and there was no drugaccumulation in human body. A dose-dependent suppression of free IgE was observedduring treatment, as a median percentage change from baseline,91.9–98.8%, in the threesingle-dose groups. Total IgE (free IgE and CMAB007:IgE complexes) concentrationsincreased in a dose-dependent fashion after administration of CMAB007.Because subcutaneous administration of CMAB007was well-tolerated and decreasedserum free IgE in a dose-dependent fashion, the results suggest that CMAB007should bean effective therapy for asthma and other allergic diseases, which are correlated withantigen-specific IgE levels.