# Structure-Guided Design of Broadly Neutralizing Lassa Virus BiSpecific Antibodies

> **NIH NIH R01** · ZALGEN LABS, LLC · 2022 · $1,192,954

## Abstract

“Structure-Guided Design of Broadly Neutralizing Lassa Virus BiSpecific Antibodies”
ABSTRACT
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. We now propose to utilize the structural information of BNhMAbs complexed with GPC to
engineer human bi-specific antibodies (BsAbs) 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 with a bi-specific
antibody results in superior protection, even at 10-fold lower doses than previoulsy tested for individual
BNhMAbs (Preliminary Results). Our proposed project meets the strict requirements of RFA-AI-17-026 in
that the LASV BsAbs are based on previously identified, well-characterized, candidate therapeutic hMAbs
against an NIAID listed emerging pathogen, LASV. The project will address a particular interest of RFA-AI-
17-026 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.” In Milestone 1 we will down-select BsAbs targeting base, middle, and cap neutralizing
epitopes on LASV GPC. In Milestone 2 dose and dosing interval studies with mono and combination BsAb
therapy in GP and NHP will be evaluated. In Milestone 3 Chemistry, Manufacturing and Control Data (CMC)
will be established for leading BsAbs. In Milestone 4 we will perform Preclinical Phar...

## Key facts

- **NIH application ID:** 10306341
- **Project number:** 5R01AI141251-04
- **Recipient organization:** ZALGEN LABS, LLC
- **Principal Investigator:** Luis Manuel Branco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,192,954
- **Award type:** 5
- **Project period:** 2018-12-24 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306341

## Citation

> US National Institutes of Health, RePORTER application 10306341, Structure-Guided Design of Broadly Neutralizing Lassa Virus BiSpecific Antibodies (5R01AI141251-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10306341. Licensed CC0.

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