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

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 previously identified sequence families that bound and partially neutralized CD38 on cells and partial-blocking UniAbs, to be combined into a single viable drug candidate. These studies will provide novel and clinically relevant knowledge of fibrosis and critical pre-clinical data regarding SSc and other untreatable diseases characterized by unresolving fibrosis.NARRATIVE Systemic sclerosis is a chronic orphan disease with no effective treatment, associated with inflammation and thickening/scarring of skin, lungs and other organs resulting in their failure. This project introduces a novel therapeutic option of targeting a recently discovered key protein in the disease, by an efficacious therapeutic antibody that can simultaneously target it on multiple fronts, to be developed using TeneoBio’s platform of fully human heavy chain only antibodies produced in rats and identified via computational and experimental pipeline.