# Preclinical Evaluation of Advanced Pan-Lassa Immunotherapeutic Cocktails

> **NIH NIH U19** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2021 · $1,831,899

## Abstract

Lassa fever (LF) is an often-fatal viral hemorrhagic fever (VHF) endemic in West Africa. A combination of three
broadly neutralizing human monoclonal antibodies (BNhMAbs) derived from West African patients who
survived LF (Arevirumab-3) rescued 100% of nonhuman primates (NHPs), even after delay in initiation of
treatment to 8 days post-infection. Recently, we solved the crystal structure of the pre-fusion form of the Lassa
virus glycoprotein complex (GPC) bound to a BNhMAb, the first structure for the virion configuration of the
GPC of any arenavirus. Additional newly solved structures for GPC:BNhMAb complexes and derivation of
escape mutants have informed the design and evaluation of optimally formulated BNhMAb cocktails targeting
independent neutralizing epitopes. We plan to expand upon this extensive body of work to support completion
of pre-clinical evaluation of Arevirumab-3 and functionally enhanced derivatives with improved
pharmacological properties toward first-in-human clinical studies with this novel class of LF therapeutics. In
studies proposed under Specific Aim 1, we will complete the pre-clinical evaluation of Arevirumab-3.
Completion of Chemistry, Manufacturing and Control Data (CMC), preclinical pharmacology and toxicology in
animal models of LF, including prophylactic interval and recrudescence evaluations, will enable the filing of an
Investigational New Drug (IND) application toward clinical studies with Arevirumab-3 The protective activity of
non-neutralizing LASV huMAbs in animal models of LF will be evaluated in studies proposed in Specific Aim
2. The protective efficacy of non-neutralizing LASV huMAbs will be evaluated and down-selected in guinea
pigs. If non-neutralizing protective huMAbs (NNPhuMAbs) are identified, the activity of this class of antibodies
will be further evaluated in NHP models of LF, either individually or in rationally designed cocktails. In studies
proposed under Specific Aim 3, we will design enhanced immunotherapeutics via Fc effector and
computational optimization, bi-specific antibody engineering (BsAbs), “designer” production cell lines that
attach specific glycans, and surveillance data inputs. Enhancement of immunotherapeutic cocktails with Fc
engineering, evaluation of BsAbs, machine learning algorithms, and CRISPR/Cas9-based generation of NS0
or CHO production cell lines with designer modifications will define characteristics of next generation LF
immunotherapeutics. Surveillance of circulating and emerging clinical LASV strains will educate the design of
LF immunotherapeutics with robust clinical characteristics and sustained potency. Under Specific Aim 4, we
propose studies to valuate in vivo protection and PK of optimized BNhMAbs, NNPhMAbs, and BsAbs. In vivo
evaluation of optimized LASV antibodies in established models of LF will educate advanced pre-clinical
evaluation of second generation immunotherapeutics with improved pharmacological properties. The studies
proposed in Project 1 are ...

## Key facts

- **NIH application ID:** 10158449
- **Project number:** 5U19AI142790-03
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Robert F Garry
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,831,899
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158449

## Citation

> US National Institutes of Health, RePORTER application 10158449, Preclinical Evaluation of Advanced Pan-Lassa Immunotherapeutic Cocktails (5U19AI142790-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10158449. Licensed CC0.

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