# Development of antibody drug conjugates as pan-filo antivirals

> **NIH NIH R43** · MICROBIOTIX, INC · 2024 · $286,708

## Abstract

Project Summary
Filoviruses cause severe hemorrhagic fevers and are among the deadliest human viruses with no approved
treatment or prophylactic options. Periodic outbreaks, such as the recent epidemic of Ebola virus (EBOV) in
West Africa, exhibit mortality rates ranging from 50-90%. They are classified as “Category A priority bioweapon
agents” by the Centers for Disease Control and Prevention. The most advanced candidates for anti-filovirus
therapy with proven efficacy in non-human primates (NHPs) utilize RNA interference (RNAi), high dose mixtures
of monoclonal antibodies (mAbs), or repurposed influenza, herpes or hepatitis C inhibitors. Although they
represent important advances, these approaches have serious limitations including the high therapeutic doses
required (20-30 g of mAb/patient), limited spectrum (primarily Zaire ebolavirus) and/or narrow therapeutic
windows (small molecules/RNAi).
Building on recent work demonstrating the critical nature of endosomal interactions between the filoviral
glycoprotein (GP) and the host cholesterol transport protein Niemann-Pick C1 (NPC1) for filoviral entry, we have
developed antibodies and small molecules that disrupt this mechanism to inhibit viral entry. These include
several bispecific GP-targeting pan-ebolavirus broadly neutralizing antibodies (bNAbs) efficacious in multiple
animal models, with down-selection to a final cocktail based on NHP efficacy underway. In parallel, we identified
a phenylpiperazine compound MBX-5321, which inhibits the GP-NPC1 interaction to block infections of virulent
EBOV, SUDV and MARV at nM concentrations in vitro, demonstrates excellent PK/PD properties, exhibits
excellent murine tolerability, has established efficacy in mice, and is currently being optimized for a targeted IND.
In this proposal we will tether MBX-5321 to bispecific pan-filo bNABs to make broad-spectrum antibody-drug
conjugates (ADCs) that synergistically inhibit viral entry.
The objective of this proposal is to demonstrate that these ADCs will provide improved efficacy and selectivity
for filovirus treatment over either agent alone, providing highly efficacious pan-filo agents, broadening the
therapeutic window and easing drug stockpiling efforts. We will accomplish this objective through three specific
aims: In Aim 1 we will synthesize and complete physical characterization of >40 ADCs demonstrating serum
stability with efficient endosomal release. In Aim 2 we will prioritize ADCs through in vitro analysis of pan-filovirus
inhibitory activity. In Aim 3 we prioritize ADCs for PK and toxicity and evaluate two pan-filovirus ADCs for in vivo
efficacy in a mouse model of EBOV infection.

## Key facts

- **NIH application ID:** 10911352
- **Project number:** 5R43AI179343-02
- **Recipient organization:** MICROBIOTIX, INC
- **Principal Investigator:** Gai Liu
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $286,708
- **Award type:** 5
- **Project period:** 2023-08-21 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911352

## Citation

> US National Institutes of Health, RePORTER application 10911352, Development of antibody drug conjugates as pan-filo antivirals (5R43AI179343-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10911352. Licensed CC0.

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