Lassa fever (LF) 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, recorded geographic expansion of rodent reservoirs, ease of procurement and weaponization of the virus, and the recent emergence of new Lassa virus (LASV) strains support recommendations for enhanced preparedness for LF.
We isolated and characterized 113 human monoclonal antibodies (hMAbs), the first large panel of human antibodies 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 glycoprotein complex (GPC) trimer.
LASV is genetically diverse with four distinct lineages present in West Africa. Some hMAbs neutralized all 4 LASV lineages. Challenge of outbred guinea pigs (GP) in a model of lethal LF informed the down-selection of broadly neutralizing hMAbs (BNhMAbs) for studies in a nonhuman primate (NHP) model, Cynomolgus macaques. A combination of 3 BNhMAbs, each with broad neutralizing activity and recognition of distinct epitopes on the LASV GPC, 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. The 3 BNhMAb cocktail conferred 100% protection in NHP against lethal challenge with LASV strains from lineages II and IV. Combined walkout studies with dose-down administration of 2 or 3 BNhMAb combinations revealed superior protection with the cocktails at 1.5 mg/Kg, highlighting the potency of the therapeutic and its viability as a treatment for a neglected viral tropical disease.
We have subsequently utilized the structural information of BNhMAbs complexed with GPC to engineer bi-specific hMAbs that span two highly protective epitopes, thereby reducing the number of molecules required to confer superior protection against LF. Preliminary results in LASV-challenged GP suggest that targeting quaternary neutralizing epitopes in the base of GPC, above the membrane proximal external region (MPER), with a bi-specific antibody results in superior protection, even at 10-fold lower doses than previoulsy tested for individual BNhMAbs. LASV bi-specific BNhMAbs (Bi-BNhMAbs) are based on previously identified, well-characterized, candidate therapeutic hMAbs against an NIAID listed emerging pathogen 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 plan to complete preclinical evaluation of a first-in-class immunotherapeutic Bi-BNhMAb for the prophylactic and post-exposure treatment of LF within the next 2 years.
Intellectual property ownership of the antibodies, 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 and its next generation derivatives.
(1) Cross, et.al. (2016) Treatment of Lassa virus infection in outbred guinea pigs with first-in-class human monoclonal antibodies. Antiviral Research 133: 218-222.
(2) Mire, et.al. (2017) Human-monoclonal-antibody therapy protects nonhuman primates against Lassa fever. Nature Medicine, doi 10.1038/nm.4396