# Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity

> **NIH NIH R42** · AQUALUNG THERAPEUTICS CORP. · 2024 · $975,215

## Abstract

ABSTRACT
Inflammatory bowel disease (IBD) is a debilitating disease (without curative therapies) that is critically influenced
by dysregulated inflammatory pathways. This A0 R42 STTR application focuses on a highly novel humanized
monoclonal antibody (mAb), ALT-100, to target and neutralize eNAMPT (extracellular nicotinamide
phosphoribosyltransferase), a damage-associated molecular pattern protein (DAMP) that robustly activates
innate immunity-driven inflammatory pathways via ligation of the Toll-like receptor 4 (TLR4). We speculate
the eNAMPT-neutralizing ALT-100 mAb to be a strategy to address the unmet need for therapies that limit
inflammatory bowel injury/fibrosis and reduce the severity of IBD. Published and unpublished data strongly
support involvement of eNAMPT in human IBD pathobiology. First, NAMPT RNA and protein expression are
significantly increased in intestinal tissues from IBD patients and are highly upregulated by IBD-relevant stimuli
including growth factors and cytokines. Second, plasma/serum eNAMPT levels are elevated in IBD subjects
and correlate with disease severity and responses to anti-TNFa therapies. Thirdly, NAMPT polymorphisms
(SNPs), previously linked to inflammatory disease severity in ARDS and pulmonary hypertension (PH),
associate with IBD severity in GWAS studies. Lastly, compellingly published data demonstrate eNAMPT is a
highly druggable target, with ALT-100 mAb profoundly attenuating multiple preclinical systemic
inflammation/organ injuries (ARDS, PH, radiation-induced fibrosis, cancer). Importantly, ALT-100 mAb
reduces preclinical IBD severity, colon inflammation and fibrosis. The feasibility of ALT-100 mAb as an
IBD therapy is supported by completed acute IND-enabling pharmacokinetic (PK) studies and 28-day toxicity
studies showing the IV ALT-100 mAb formulation has a T1/2 half-life of 10 days and is without discernable toxicity
(rats and pigs). In addition, we have completed CMC manufacturing development (stable cell line,
Research/Master Cell Banks) and a 200L GMP Bioreactor run (expression 6 gms/L) of the IV ALT-1000 mAb
formulation (10mg/mL). We anticipate FDA IND submission for ARDS in May 2022. In PHASE I of this R-42
STTR PHASE I/II Fast Track application, Specific Aims #1/2 will assess pharmacodynamic (PD) properties of
ALT-100 mAb in well-established acute (7 days) and chronic (28 days) preclinical DSS-induced murine colitis
models and optimize ALT-100 mAb dosing (0.4 mg/kg, 1mg/kg, 4 mg/kg) and route of delivery (IV vs subQ)
using IV formulations (10 mg/mL) and subQ formulations (100 mg/mL). In PHASE II studies conducted in rats
and minipigs, Specific Aim #3 will characterize the pharmacokinetic (PK) characteristics of the subQ and IV
ALT-100 mAb formulations and Specific Aim #4 will evaluate chronic subQ ALT-100 mAb toxicokinetic
properties. Successful completion of these PHASE I/ II STTR studies will establish ALT-100 mAb as a viable
IBD therapeutic and enable the submission of an FDA IND applicat...

## Key facts

- **NIH application ID:** 10907806
- **Project number:** 5R42DK135208-03
- **Recipient organization:** AQUALUNG THERAPEUTICS CORP.
- **Principal Investigator:** Joe G. N. Garcia
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $975,215
- **Award type:** 5
- **Project period:** 2022-09-19 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907806

## Citation

> US National Institutes of Health, RePORTER application 10907806, Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity (5R42DK135208-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10907806. Licensed CC0.

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