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

抗 CD38 抗体抑制 CD38 NADase：系统性硬皮病的一种新疗法

基本信息

批准号：
9975609
负责人：
Willem van Schooten
金额：
$ 22.12万
依托单位：
TENEOBIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975609
关键词：
Address Affinity Aging Animals Antibodies Apoptosis Attenuated Authorization documentation Avidity Binding Binding Sites Biological Biological Availability Biology Biopsy Bleomycin Cell Aging Cells Chronic Cicatrix Clinic Clinical Data Clinical Research Collaborations Collagen Consumption Data Deacetylase Development Disease Effector Cell Elements Enzymes Failure Family Fibrosis Future Goals Grant Human Hydrolase Immune In Vitro Inflammation Knowledge Lead Longevity Lung Lysine Mediator of activation protein Metabolic Metabolism Modeling Monoclonal Antibodies Multiple Myeloma Mus Myofibroblast NAD+ Nucleosidase Nicotinamide Mononucleotide Nicotinamide adenine dinucleotide Organ Patients Phase Proteins Rare Diseases Rattus Safety Serum Skin Stress Stromal Cells Structure Supplementation Systemic Scleroderma T-Lymphocyte Testing Therapeutic Therapeutic antibodies Tissues Toxic effect Transgenic Mice Universities age related base bioinformatics pipeline clinical candidate clinically relevant drug candidate effective therapy in vivo inhibitor/antagonist manufacturability mouse model novel novel strategies novel therapeutics pre-clinical prevent skin fibrosis treatment response

项目摘要

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.

抽象的 Teneobio 的抗体 (Ab) 开发专家将与西北大学系统性硬化症研究所联手（SSc），肌成纤维细胞和烟酰胺腺嘌呤二核苷酸（NAD）代谢专家，利用最近将 CD38 抑制作为纤维化治疗范例推向临床的新发现；开发选择性阻断 CD38 NADase 的全人重链多价/双互补位抗体活性，同时保持 CD38+ 细胞完整 SSc 是一种与炎症和相关的慢性孤儿疾病。皮肤、肺和其他器官的纤维化，导致它们失效的关键效应器是肌成纤维细胞。 SSc 患者表现出细胞衰老的特征，包括细胞衰老的特征，其起源和持续因素尚不清楚。皮肤和肺中与长寿相关的 SIRT 赖氨酸脱乙酰酶活性抑制肌成纤维细胞。激活并受到 NAD+ 生物利用度的严格调节，NAD+ 生物利用度的缺乏是与年龄相关的功能和 CD38 是导致衰老过程中 NAD+ 生物利用度降低的主要 NMNase/NADase。同样，在 SSc 模型中，组织和血清中的 NAD+ 水平降低，CD38 显着上调，如与 SSc 皮肤活检一样，在基质细胞中，CD38 具有直接促纤维化作用，导致持续性肌纤维化。成纤维细胞活化和纤维化；同时选择性抑制 CD38 NADase，在体外和体外显示出抗纤维化作用因此，我们追求抑制CD38 NADase活性可以预防和逆转组织NAD+。消耗并减轻多器官纤维化，因此对 SSc 纤维化治疗有很大希望。复合抑制剂和抗 CD38 单克隆抗体不适合 SSc，需要一种新的方法。 Teneobio 开发了一个基于 (i) 全人类重链抗体 (UniAbs) 的平台；(ii) 高通量； NGS 生物信息学管道；以及 (iii) 产生 UniAb 的专有大鼠结构促进多价。结合力、稳定性、卓越的安全性及其小的结合位点非常适合酶阻断。 Teneobio 鉴定出可抑制人 CD38 的 UniAb 组合，以及替代抗鼠 CD38 UniAb 能力提高体内组织和血清中的烟酰胺单核苷酸 (NMN) 和 NAD+ 的具体目标#1。该项目将重点使用针对 CD38 酶活性的 UniAb 进行体内小鼠概念验证研究，以测试其对老年和年轻博来霉素纤维化模型小鼠的水解酶抑制是否可以增强组织 NMN 和 NAD 可以减少多个器官的纤维化和炎症，并且是否随年龄增长而增加； CD38 在老年小鼠纤维化器官中的表达将导致有效的治疗反应，这将促进阶段。 II IND 对 SA#2 中确定的临床候选药物进行动物研究将侧重于识别。使用先前鉴定的序列对人类 CD38 的高亲和力酶阻滞剂进行表征结合并部分中和细胞上的 CD38 和部分阻断 UniAb 的家族，将组合成一个这些研究将提供有关纤维化和临床相关的新颖知识。关于 SSc 和其他以未解决的纤维化为特征的无法治疗的疾病的关键临床前数据。