?Preclinical evaluation of a potent Lassa fever immunotherapeutic antibody cocktail? ABSTRACT Lassa fever is an often-fatal viral hemorrhagic fever (VHF) that is endemic in West Africa where it causes significant social and economic disruption. The lack of an approved therapeutic or vaccine, potential for geographic expansion of the rodent reservoir, ease of procurement and weaponization of the virus, and the recent emergence of new Lassa virus (LASV) strains support recommendations for enhanced preparedness for Lassa fever (LF). We isolated and characterized over 113 human monoclonal antibodies (MAbs) from memory B cells of Lassa fever survivors, the first large panel of human MAbs against LASV described. We found that the most potent neutralizing hMAbs target quaternary epitopes that require both GP1 and GP2 subunits of each monomer in the trimer. LASV is genetically diverse with four distinct lineages present in West Africa. Some hMAbs neutralized all four LASV lineages. Bicistronic IgG1 backbone vectors for high level stable expression in mammalian cells were used to generate sufficient quantities of the neutralizing hMAbs (BNhMAbs) for therapeutic evaluation using the CHOLCelect system (www.zalgenlabs.com/technology.html). Challenge of outbred guinea pigs (GP) in a model of lethal LF informed the down-selection of BNhMAbs for studies in a nonhuman primate (NHP) model, Cynomolgus macaques. A combination of three BNhMAbs, each with broad neutralizing activity and recognition of distinct epitopes on the LASV glycoprotein complex, rescued 100% of NHPs even after delay in the start of treatment to 8 days post-infection, a time when the animals displayed severe hematological and metabolic dysregulation. Our proposed project meets the strict requirements of RFA-AI-16-034 in that the LASV BNhMAb combo is a previously-identified, well-characterized, candidate therapeutic against an NIAID listed emerging pathogen, LASV. The project will address a particular interest of RFA-AI-16-034 for immunotherapeutics that would ?enable prevention of infection or intoxication in the face of an immediate threat, protection of immunocompromised individuals, or post-exposure treatment to suppress infection and disease.? We have named the LASV BNhMAb immunotherapeutic cocktail ?Arevirumab? based on guidance from the International Nonproprietary Name (INN) Working Group and the USAN Council (USANC) on monoclonal antibody nomenclature scheme language guidelines. In Milestone 1 we will perform dose finding and dosing interval studies with single LASV BNhMAbs and Arevirumab therapy in guinea pigs and Cynomolgus macaques, both established models of lethal Lassa fever. Chemistry, Manufacturing and Control (CMC) data will be generated in Milestone 2. In Milestone 3 we will perform preclinical pharmacology and toxicology of Arevirumab in appropriate animal models. At the conclusion of the proposed program we will enter clinical evaluation of a first-in-class immunotherapeutic cocktail of human monoclonal antibodies for the prophylactic and post-exposure treatment of Lassa fever. Intellectual property ownership of the antibodies and biopharmaceutical manufacturing technologies, and the capacity to perform therapeutic clinical studies in infected patients from endemic LF regions establishes a commercially feasible path for Arevirumab. This application contains proprietary/priviledged information that Tulane University and its subcontractors request not be released to persons outside the Government, except for the purposes of review and evaluations.
?Preclinical evaluation of a potent Lassa fever immunotherapeutic antibody cocktail? NARRATIVE This proposal will advance the preclinical evaluation of Arevirumab, a combination of broadly neutralizing human monoclonal antibodies that has been shown to rescue 100% of nonhuman primates even after delay in the start of treatment to 8 days post-infection, a time when the animals displayed severe hematological and metabolic dysregulation. We will perform dose finding and dosing interval studies, generate Chemistry, Manufacturing and Control (CMC) data and perform preclinical pharmacology and toxicology of Arevirumab in appropriate animal models. At the conclusion of the proposed program we will enter clinical evaluation of a first-in-class immunotherapeutic cocktail of human monoclonal antibodies for the prophylactic and post- exposure treatment of Lassa fever.
| Mire, Chad E; Cross, Robert W; Geisbert, Joan B et al. (2017) Human-monoclonal-antibody therapy protects nonhuman primates against advanced Lassa fever. Nat Med 23:1146-1149 |
