HCMV Therapeutic Antibody Safety Trial

Abstract Human cytomegalovirus (HCMV) transmission from mother to fetus is implicated in ~15% of stillbirths and ~16,000 birth defects annually in the US. HCMV is also the major viral cause of medical complications associated with bone marrow and organ transplantation. Passive immunization using anti-HCMV enriched human immune globulin (HIG) has shown promising activity for both indications. HIG is a complex, variable product that may cause side effects from off-target antibody binding. A monoclonal antibody (mAb) offers qualitative advantages over HIG including potency, safety, production efficiency and quality control. Trellis Bioscience has discovered a high affinity native human mAb (TRL345) against the most conserved site on the HCMV virion (gB AD-2 Site I). TRL345 is a human IgG1kappa (G1m1,17 (z,a); Km3 allotype) monoclonal antibody cloned from human B lymphocytes. This mAb neutralized 15 out of 15 clinical isolates of all four major serotypes. It protected all of the specialized cell types relevant to human pathology. It was also fully protective in a model of human placental fragments grown as tissue explants ex vivo. This published work was completed under a Phase I/II SBIR grant. A Master Cell Bank has been developed that expresses TRL345 in CHO cells at a commercially useful level (1.74 g/L) at the 250L GMP scale. All IND-enabling analytical work has been completed, including GLP toxicology in rats and tissue reactivity profiling. With SBIR CRP funding, the first clinical lot has been manufactured yielding sufficient material for Phase 1 and 2 human clinical trials. We propose here to conduct a Phase 1 single ascending dose clinical trial in healthy volunteers.Narrative Women who are first infected with HCMV early during pregnancy have ~12% chance that their child will be born with or later develop significant handicaps, primarily deafness but also varying degrees of cognitive and motor function deficits. This population comprises ~120,000 women annually in the US with comparable incidence in Europe and Japan. Reinfection or reactivation of latent infection also contributes to the risk of birth defects. Although harder to detect, and thus less suitable for a clinical trial, the potential benefit of TRL345 likely extends to the entire population of first trimester pregnancies. The economic impact of congenital HCMV, including the costs of medical care and educational expenses, is estimated to be andgt;$3 billion annually (US). HCMV is also the leading viral cause of hospitalization for solid organ and bone marrow transplant patients, impacting close to 50,000 patients annually in the US at a cost of ~$5 billion.