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）开发专家与Northwesty的系统性Sclleroisisis合作（SSC），肌成纤维细胞和烟酰胺腺苷二核苷酸（NAD）代谢专家，以利用最近的将CD38推向纤维化中的新发现，以最终目标遗传纤维化；仅开发完全人类的重链，仅可选的多价/双型AB可阻止CD38 NADase 在离开CD38+细胞完整的同时，SSC是一种与炎症相关的慢性孤儿皮肤，肺部和其他器官的纤维骨质，导致其衰竭。起源和持续性因素是未知的。寿命相关的SIRT赖氨酸在皮肤和肺中的活性。激活，并由NAD+生物利用度紧密地定制，其缺乏与年龄相关的功能和代谢下降。同样，在SSC模型中，组织和血清中的NAD+水平降低，CD38显着上调，如在基质细胞中的SSC皮肤活检中，CD38具有直接的纤维化作用在选择性CD38 NADASE的情况下，肥大的激活和纤维化，在体外显示抗野性因此，我们假设CD38 NADase活性可以预防和反向NAD+ 部署和衰减多器官纤维化，因此对SSC纤维化治疗的前景很高复合抑制剂和抗CD38单克隆ABS不适合SSC，因此需要采用新颖的方法。 Teneobio开发了一个基于（i）完全人体重链ABS（UNIAB）的平台； NGS生物信息学管道；结合，稳定性，优越的安全剖面和Teir小结合位点非常适合酶阻滞。 Teneobio鉴定了抑制人CD38的UNIABS组合和替代抗Murinecd38 Unibaber 在组织中竞争烟酰胺单核苷酸（NMN）和NAD+。项目将使用针对CD38酶促行为的单胞菌进行体内鼠概念证明研究测试其在两种古老的Youycin纤维化模型小鼠中的水解酶抑制是否都可以增强组织 NMN和NAD并减少多个器官的纤维化和炎症；旧小鼠的纤维化器官中的CD38表达将导致整数治疗反应。 II启用SA＃2中确定的临床候选者的动物研究将集中在识别上并使用先前鉴定的序列来表征人CD38的高亲和力酶阻滞剂在细胞和部分阻滞大学上结合和部分中和CD38的家族，将其合并为单一可行的药物。有关SSC和其他以无法解决的FIROSIS为特征的有关SSC和其他不可治疗疾病的关键临床前数据。