Monoclonal antibodies for the treatment of Ebola virus disease.

INTRODUCTION: To date, the management of patients with suspected or confirmed Ebolavirus disease (EVD) depends on quarantine, symptomatic management and supportive care, as there are no approved vaccines or treatments available for human use. However, accelerated by the recent large outbreak in West Africa, significant progress has been made towards vaccine development but also towards specific treatment with convalescent plasma and monoclonal antibodies. Areas covered: We describe recent developments in monoclonal antibody treatment for EVD, encompassing mAb114 and the MB-003, ZMAb, ZMapp™ and MIL-77E cocktails. Expert opinion: Preventive measures, are, and will remain essential to curb EVD outbreaks; even more so with vaccine development progressing. However, research for treatment options must not be neglected. Small-scale animal and individual human case studies show that monoclonal antibodies (mAbs) can be effective for EVD treatment; thus justifying exploration in clinical trials. Potential limitations are that high doses may be needed to yield clinical efficacy; epitope mutations might reduce efficacy; and constant evolution of (outbreak-specific) mAb mixtures might be required. Interim advice based on the clinical experience to date is that treatment of patients with mAbs is sensible, provided those could be made available in the necessary amounts in time.

Severe combined immunodeficiency (SCID) mouse modeling of P-glycoprotein chemosensitization in multidrug-resistant human myeloma xenografts.

We have established a reproducible in vivo model of human multiple myeloma in the severe combined immunodeficiency (SCID) mouse using both the drug-sensitive 8226/S human myeloma cell line and the P-glycoprotein-expressing multidrug-resistant 8226/C1N subline. As demonstrated previously, the SCID mouse is well suited as a model for myeloma because: (a) human SCID xenografts are readily attained; (b) human myeloma xenografts are readily detected by their immunoglobulin secretion; and (c) differential therapy effects in drug-sensitive versus drug-resistant cell lines are readily demonstrable by monitoring mouse urinary human immunoglobulin output. In the current study, we have utilized this model to evaluate the in vivo efficacy of chemomodulators of P-glycoprotein-related multidrug resistance. In our initial experiments, doxorubicin alone was effective in treating the 8226/S human myeloma xenografts but had no effect on the drug-resistant 8226/C1N xenografts, in the absence of the chemosensitizing agent verapamil. In subsequent experiments, the combination of verapamil and doxorubicin resulted in both a decrease in human lambda light chain urinary excretion and an increase in survival of those animals bearing the 8226/C1N tumor. The median survival time of animals injected with 8226/C1N cells and subsequently treated with doxorubicin was 48.6 +/- 7 days, which compared to a survival of 89.6 +/- 18 days in animals receiving the 8226/S cell line and treated with doxorubicin alone (P < 0.001). When verapamil was added to the treatment regimen of those animals bearing the 8226/C1N xenografts, there was a 179% increase in their life span (P < 0.001), which corresponded with the observed decreased light chain in the urine. In animals receiving multiple courses of chemotherapy, an attenuated response to verapamil and doxorubicin was observed, in a manner analogous to the clinical setting of human drug-resistant myeloma escape from chemosensitivity. The SCID human myeloma xenograft model thus offers a means of evaluating the in vivo efficacy and potential toxicities of new therapeutic approaches directed against P-glycoprotein in multidrug-resistant human myeloma.