Nipah virus (NiV) and Hendra virus (HeV) are closely related viral zoonoses that form the genus Henipavirus in the family Paramyxoviridae. They are enveloped, negative-sense RNA viruses that cause a systemic and fatal disease in a variety of animal hosts and in humans. They are classified as biological safety level-4 (BSL4) viruses and possess several characteristics, such as the ability to be transmitted via aerosol that justifies their listing as Category C biothreat agents by the NIH and CDC. There is currently no approved therapeutics against either NiV or HeV and death is certain for approximately 75% of the cases. Ribavirin has been used against HeV and NiV with no effect. We have identified a fully human monoclonal antibody, m102.4, that potently neutralizes all available NiV and HeV isolates in vitro and provided post-exposure protection of ferrets from NiV challenge and of African Green Monkeys (AGM) from HeV challenge. We believe that m102.4 would, therefore, provide an effective post-exposure prophylactic against both NiV and HeV. Our objective here is to produce sufficient quantities to perform IND-supportive pharmacology, toxicology and efficacy studies as necessary steps in its preclinical development. We plan to pursue our objective through the following specific aims: 1) Develop analytical characterization methods for m102.4;2) Manufacture m102.4;3) Perform preclinical toxicology and pharmacokinetic studies;and 4) Determine the minimal protective dose and its therapeutic window in ferret and AGM challenge models. By the end of the funding period, we will have (i) prepared a characterized research-grade """"""""pre-seed"""""""" for use to manufacture a m102.4 Master Cell Bank, (ii) optimized a development-scale process suitable for the manufacturing of cGMP clinical trial materials, (iii) manufactured more than 60 grams of development-grade m102.4 drug substance to perform IND supportive pharmacokinetic, toxicology, and efficacy studies, and (iv) executed said studies. Subsequent applications will pursue full cGMP manufacture of 1) a master cell bank and 2) antibody for Phase 1 clinical evaluation. Profectus BioSciences, Inc. has the necessary development and outsourcing expertise, experience and quality systems in place that will be needed to support these activities proposed under subsequent applications. Public Health Relevance: Nipah virus (NiV) and Hendra virus (HeV) are closely related viral zoonoses that are associated with significant morbidity and mortality in both animals and humans. They are listed as Category C biothreat agents by the NIH and CDC, because they can be isolated from their natural reservoir, easily grown to large amounts in cell lines under general laboratory conditions, and transmitted via aerosol. Recent outbreaks indicate that the viruses are highly virulent and lethal: HeV and NiV infections lead to death in 75% of the cases. There are currently no approved products that prevent or treat NiV or HeV infections. An anti- HeV and NiV human monoclonal antibody, m102.4, has engendered complete protection from challenge with either of NiV or HeV in 2 animal models, one of which is non-human primate. With this application we intend to carry on preclinical testing for safety and determine an efficacy administration regiment in both animal models. While manufacturing of the antibody product, we will produce a characterized research-grade """"""""pre-seed"""""""" cell line for use to manufacture m102.4 Master Cell Bank and develop QA/QC methods for the antibody characterization, purification, identity and stability suitable for the manufacturing of future cGMP clinical trial material.
Nipah virus (NiV) and Hendra virus (HeV) are closely related viral zoonoses that are associated with significant morbidity and mortality in both animals and humans. They are listed as Category C biothreat agents by the NIH and CDC, because they can be isolated from their natural reservoir, easily grown to large amounts in cell lines under general laboratory conditions, and transmitted via aerosol. Recent outbreaks indicate that the viruses are highly virulent and lethal: HeV and NiV infections lead to death in 75% of the cases. There are currently no approved products that prevent or treat NiV or HeV infections. An anti- HeV and NiV human monoclonal antibody, m102.4, has engendered complete protection from challenge with either of NiV or HeV in 2 animal models, one of which is non-human primate. With this application we intend to carry on preclinical testing for safety and determine an efficacy administration regiment in both animal models. While manufacturing of the antibody product, we will produce a characterized research-grade pre-seed cell line for use to manufacture m102.4 Master Cell Bank and develop QA/QC methods for the antibody characterization, purification, identity and stability suitable for the manufacturing of future cGMP clinical trial material.
