# Inhibition of CD38 NADase by anti-CD38 antibody: a novel therapy for systemic scleroderma

> **NIH NIH R43** · TENEOBIO, INC. · 2020 · $221,204

## Abstract

ABSTRACT
Teneobio’s antibody (Ab) development experts will join forces with Northwestern University’s systemic sclerosis
(SSc), myofibroblasts and nicotinamide adenine dinucleotide (NAD) metabolism experts, to capitalize on recent
novel findings to advance CD38 inhibition as a therapeutic paradigm in fibrosis into the clinic; with the end goal
of developing a fully human heavy chain only multivalent/biparatopic Ab that selectively blocks CD38 NADase
activity while leaving CD38+ cells intact. SSc is a chronic orphan disease associated with inflammation and
fibrosis of skin, lungs and other organs, resulting in their failure. SSc key effectors are myofibroblasts but their
origin and persistence factors are unknown. SSc patients display hallmarks of cellular aging, including diminished
activity of longevity-associated SIRT lysine deacetylases in skin and lung. SIRT activity inhibits myofibroblasts
activation and is tightly regulated by NAD+ bioavailability, shortage of which underlies age-related functional and
metabolic decline. CD38 is the principal NMNase/NADase responsible for reduced NAD+ bioavailability in aging.
Similarly, NAD+ levels in tissue and serum are reduced and CD38 is significantly upregulated in SSc models, as
wells as in SSc skin biopsies. In stromal cells, CD38 had a direct profibrotic effect, leading to persistent myofi-
broblast activation and fibrosis; while selective CD38 NADase inhibition, showed anti-fibrotic effects in vitro and
in vivo. Therefore, we hypothesize that CD38 NADase activity inhibition can prevent and reverse tissue NAD+
depletion and attenuate multiorgan fibrosis, thus holding high promise for SSc fibrosis treatment. Current small
compound inhibitors and anti-CD38 monoclonal Abs are unsuitable for SSc, necessitating a novel approach.
Teneobio developed a platform based on (i) fully human heavy chain only Abs (UniAbs); (ii) high-throughput
NGS bioinformatics pipeline; and (iii) proprietary UniAb-producing rats. UniAbs’ structure facilitates multivalent
binding, stability, superior safety profiles, and their small binding sites are uniquely suited for enzyme blockade.
Teneobio identified UniAbs combinations inhibiting human CD38, and a surrogate anti-murineCD38 UniAb able
to raise nicotinamide mononucleotide (NMN) and NAD+ in tissues and serum in vivo. Specific Aim #1 of this
project will focus on in vivo murine proof-of-concept studies using UniAbs targeting CD38 enzymatic activity, to
test whether its hydrolase inhibition in both old and young bleomycin-fibrosis model mice can augment tissue
NMN and NAD and reduce fibrosis and inflammation in multiple organs; and whether the age-dependent rise in
CD38 expression in fibrotic organs of old mice will lead to potent therapeutic response. This will facilitate Phase
II IND enabling animal studies for clinical candidates identified in SA#2. Specific Aim #2 will focus on identification
and characterization of high-affinity enzymatic blockers of human CD38, using pre...

## Key facts

- **NIH application ID:** 9975609
- **Project number:** 1R43AR077336-01
- **Recipient organization:** TENEOBIO, INC.
- **Principal Investigator:** Willem van Schooten
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $221,204
- **Award type:** 1
- **Project period:** 2020-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975609

## Citation

> US National Institutes of Health, RePORTER application 9975609, Inhibition of CD38 NADase by anti-CD38 antibody: a novel therapy for systemic scleroderma (1R43AR077336-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975609. Licensed CC0.

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