Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

Abstract

Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, we screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV–glycoprotein (GP) Abs. ANDV-GP–specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. We examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV-induced HCPS.

Neutralizing Monoclonal Antibodies against the Gn and the Gc of the Andes Virus Glycoprotein Spike Complex Protect from Virus Challenge in a Preclinical Hamster Model

“…To evaluate their potential as postexposure therapeutics, we utilized the Syrian hamster model of ANDV infection and tested a subset of the mAbs for protective efficacy. This model has a broad similarity to HCPS in humans, including enhanced respiratory distress, high lethality, and select tissue tropisms (24,50,51). We employed a subset of neutralizing MAbs which span the properties and epitopes explored above, namely, KL-HAP-2D11 (Gc binding, ADCC inactive), KL-AN-4E1 (Gn binding, ADCC active), KL-AN-5E8 (Gn binding, ADCC active), and KL-HAP-6B12 (Gc binding, ADCC active).…”

“…Unfortunately, MAbs, especially neutralizing and protective MAbs, are severely lacking in the hantavirus field. In a recent study conducted by Garrido et al, two anti-ANDV GnGc MAbs were successfully tested for therapeutic efficacy in animal models in a cocktail setting (24), clearly demonstrating that anti-GnGc MAbs may be useful in combatting this disease. However, the range of possible properties such MAbs may take has yet to be fully explored.…”

Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody

“…At present, treatment and prevention options for hantaviral disease remain extremely limited due to the absence of approved therapeutics. However, strides are being made towards the development of efficacious treatments, as shown by the recent development of novel mAbs against ANDV [51], and a polyclonal antibody treatment against HTNV [52], both of which demonstrate efficacy in animal models. In toto, our integrated structural and functional analysis provides a structure-based blueprint for understanding antibody-mediated neutralization of this group of emerging pathogens, and a template for the rational development of much needed biologics against this group of medically important pathogens.…”

Vaccines and Therapeutics Against Hantaviruses

“…Considering the limited availability of convalescent plasma from HCPS survivors, goose polyclonal antibodies were acquired from ANDV DNA vaccine, and the purified IgY/IgY Fc from egg yolks could protect hamsters from lethal ANDV infection. Recently, two NAbs, JL16 and MIB22, were developed from the ANDV GP-specific memory B cells of convalescent HCPS patients, both of which reached in a 100% protection rate against lethal ANDV challenge (Garrido et al, 2018). Although NAbs from convalescent patient or immunized animals could obviously restrain hantaviral infection and improve disease outcome, purified human or humanized NAbs against hantaviruses with increased security and efficacy should be developed for clinical experiments.…”