Human cytomegalovirus (HCMV) is the major viral cause of birth defects and of medical complications associated with organ transplantation. Passive immunization using human immune globulin (HIG) has been shown to prevent disease. As pooled plasma, however, HIG is a variable product that potentially contains infectious agents or may cause side effects. Native human monoclonal antibodies (mAbs), cloned from human blood, offer major advantages over HIG including safety, efficacy, potency, production efficiency and quality control. By using its advanced mAb discovery technology, CellSpot(tm), Trellis Bioscience has discovered a sub-nanomolar affinity native human mAb against HCMV glycoprotein B (gB). Neutralization studies in vitro with a virulent clinical strain, VR1814, showe that CMV345 is 5-10 fold more potent than any previously described gB mAb and several-fold more potent than HIG. It targets a strain-invariant epitope essential for infection of all cell typs, providing protection for all of the specialized cell types relevant to the human pathology including fibroblast, epithelial, endothelial and primary placental cytotropoblasts (CTBs). Trellis has collaborated with Dr. Lenore Pereira at U.C. San Francisco to establish the efficacy of CMV345 on CTBs as isolated cells in vitro and in models of the human placenta as tissue explants ex vivo or transplanted as xenografts in SCID-hu mice in vivo. These pioneering models provide a strong rationale for expecting high efficacy of this lead candidate mAb for blocking infection of the placenta, reducing the early pathogenic effects of virulent strains on placental development, and preventing virus transmission at the uterine-placental interface. Thus, CMV345 is a promising candidate for passive immune therapy to replace and improve upon HIG. We are submitting this Fast-Track application to bring CMV345 to readiness for clinical testing as expeditiously as possible. After the Phase I proof of concept experiments are completed, focused on confirming and extending the preliminary results presented here, Phase II studies will focus on IND-enabling manufacturing and on further elucidation of the mechanism of action needed to design the clinical strategy. In addition to optimizing the dose regimen using the SCID-hu model of fetal-maternal placenta interaction, we will explore utility in a model for HCMV disease in transplant recipients using human thymus/liver implants in SCID mice. The final deliverable from this project will be an IND-ready native human therapeutic antibody to HCMV, which is highly effective at preventing infection of all relevant cell types by a broad range of HCMV strains.
This Fast Track project will continue the development of candidate therapeutic antibodies to treat human cytomegalovirus infections in pregnancy and in transplant recipients. If successful, the antibodies will serve an important role in preventing the most frequent infectious cause of birth defects.
|Pereira, Lenore; Petitt, Matthew; Fong, Alex et al. (2014) Intrauterine growth restriction caused by underlying congenital cytomegalovirus infection. J Infect Dis 209:1573-84|
|Zydek, Martin; Petitt, Matthew; Fang-Hoover, June et al. (2014) HCMV infection of human trophoblast progenitor cells of the placenta is neutralized by a human monoclonal antibody to glycoprotein B and not by antibodies to the pentamer complex. Viruses 6:1346-64|
|McCutcheon, Krista M; Gray, Julia; Chen, Natalie Y et al. (2014) Multiplexed screening of natural humoral immunity identifies antibodies at fine specificity for complex and dynamic viral targets. MAbs 6:460-73|