This research study will test OT-82, which is an investigational ("research" or "experimental" ) drug. The study has two stages (Stage 1 and Stage 2). The purpose of Stage 1 is to determine the safety and tolerability and the maximum tolerated dose (MTD) or the maximum tested dose of OT-82 administered orally to participants. The purpose of Stage 2 is to determine the preliminary efficacy of OT-82 in relapsed or refractory lymphoma at the MTD or the maximum tested dose. Both parts of the study will also evaluate the pharmacokinetics (absorption, distribution, metabolism, elimination) of OT-82.
OT-82 treatment slowed the growth, reduced the size, or in some cases cured certain cancers in animal studies. It is hoped that participants with relapsed or refractory lymphoma treated with OT - 82 in this study will experience slowing tumor growth and/or reduction of tumor size.

开始日期2019-07-29

申办/合作机构

Oncotartis, Inc.

100 项与 OT-82 相关的临床结果

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100 项与 OT-82 相关的转化医学

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100 项与 OT-82 相关的专利（医药）

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项与 OT-82 相关的文献（医药）

2024-04-23·Blood advances

A molecular circuit linking the BCR to the NAD biosynthetic enzyme NAMPT is an actionable target in Richter syndrome

Article

作者: Micillo, Matilde ; Rovere, Matteo ; Deaglio, Silvia ; Vitale, Nicoletta ; Pesce, Noemi A. ; Messana, Vincenzo G. ; Vaisitti, Tiziana ; Efremov, Dimitar G. ; Martines, Claudio ; Fascì, Amelia

Abstract:

This works defines, to the best of our knowledge, for the first time a molecular circuit connecting nicotinamide mononucleoside phosphoribosyl transferase (NAMPT) activity to the B-cell receptor (BCR) pathway. Using 4 distinct xenograft models derived from patients with Richter syndrome (RS-PDX), we show that BCR cross-linking results in transcriptional activation of the nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme NAMPT, with increased protein expression, in turn, positively affecting global cellular NAD levels and sirtuins activity. NAMPT blockade, by using the novel OT-82 inhibitor in combination with either BTK or PI3K inhibitors (BTKi or PI3Ki), induces rapid and potent apoptotic responses in all 4 models, independently of their mutational profile and the expression of the other NAD biosynthetic enzymes, including nicotinate phosphoribosyltransferase. The connecting link in the circuit is represented by AKT that is both tyrosine- and serine-phosphorylated by PI3K and deacetylated by sirtuin 1 and 2 to obtain full kinase activation. Acetylation (ie, inhibition) of AKT after OT-82 administration was shown by 2-dimensional gel electrophoresis and immunoprecipitation. Consistently, pharmacological inhibition or silencing of sirtuin 1 and 2 impairs AKT activation and induces apoptosis of RS cells in combination with PI3Ki or BTKi. Lastly, treatment of RS-PDX mice with the combination of PI3Ki and OT-82 results in significant inhibition of tumor growth, with evidence of in vivo activation of apoptosis. Collectively, these data highlight a novel application for NAMPT inhibitors in combination with BTKi or PI3Ki in aggressive lymphomas.

2023-11-01·Clinical cancer research : an official journal of the American Association for Cancer Research

Inhibition of NAD+-Dependent Metabolic Processes Induces Cellular Necrosis and Tumor Regression in Rhabdomyosarcoma Models

Article

作者: Yeung, Choh ; Zhang, Yiping ; Wilson, Kelli ; Collins, Victor J ; Ji, Jiuping ; Mendoza, Arnulfo ; Yamamoto, Kazutoshi ; Lee, Unsun ; Issaq, Sameer H ; Lei, Haiyan ; Ito, Takeshi ; Shern, Jack F ; Yohe, Marielle E ; Krishna, Murali C ; McKay-Corkum, Grace B ; Neckers, Leonard M ; Thomas, Craig J ; Holland, David ; Heske, Christine M ; Karim, Baktiar O ; Vulikh, Ksenia

Abstract:

Purpose::

Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. NAMPT is necessary for efficient NAD+ production and may be exploited in cells with increased metabolic demands. We have identified NAMPT as a dependency in rhabdomyosarcoma (RMS), a malignancy for which novel therapies are critically needed. Here we describe the effect of NAMPT inhibition on RMS proliferation and metabolism in vitro and in vivo.

Experimental Design::

Assays of proliferation and cell death were used to determine the effects of pharmacologic NAMPT inhibition in a panel of ten molecularly diverse RMS cell lines. Mechanism of the clinical NAMPTi OT-82 was determined using measures of NAD+ and downstream NAD+-dependent functions, including energy metabolism. We used orthotopic xenograft models to examine tolerability, efficacy, and drug mechanism in vivo.

Results::

Across all ten RMS cell lines, OT-82 depleted NAD+ and inhibited cell growth at concentrations ≤1 nmol/L. Significant impairment of glycolysis was a universal finding, with some cell lines also exhibiting diminished oxidative phosphorylation. Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions with OT-82 treatment delivered on the clinical schedule.

Conclusions::

RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy.

2020-07-01·Leukemia1区 · 医学

OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis

1区 · 医学

Article

作者: Gupta, Mahima ; Vujcic, Slavoljub ; Somers, Klaartje ; Andrianova, Ekaterina L ; Korotchkina, Lioubov ; Antoch, Marina P ; Chernova, Olga B ; Toshkov, Ilia ; Joshi, Sangeeta ; Krasnov, Peter ; Polinsky, Alex ; Haber, Michelle ; Komarov, Pavel G ; Henderson, Michelle J ; Tian, Yuan ; Kazyulkin, Denis ; Norris, Murray D ; Gudkov, Andrei V ; Veith, Jean ; Lock, Richard B ; Middlemiss, Shiloh ; Kononov, Eugene ; Chernov, Mikhail V

Abstract:

Effective treatment of some types of cancer can be achieved by modulating cell lineage-specific rather than tumor-specific targets. We conducted a systematic search for novel agents selectively toxic to cells of hematopoietic origin. Chemical library screenings followed by hit-to-lead optimization identified OT-82, a small molecule with strong efficacy against hematopoietic malignancies including acute myeloblastic and lymphoblastic adult and pediatric leukemias, erythroleukemia, multiple myeloma, and Burkitt’s lymphoma in vitro and in mouse xenograft models. OT-82 was also more toxic towards patients-derived leukemic cells versus healthy bone marrow-derived hematopoietic precursors. OT-82 was shown to induce cell death by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of NAD synthesis. In mice, optimization of OT-82 dosing and dietary niacin further expanded the compound’s therapeutic index. In toxicological studies conducted in mice and nonhuman primates, OT-82 showed no cardiac, neurological or retinal toxicities observed with other NAMPT inhibitors and had no effect on mouse aging or longevity. Hematopoietic and lymphoid organs were identified as the primary targets for dose limiting toxicity of OT-82 in both species. These results reveal strong dependence of neoplastic cells of hematopoietic origin on NAMPT and introduce OT-82 as a promising candidate for the treatment of hematological malignancies.

项与 OT-82 相关的新闻（医药）

2022-07-05

·生物制品圈

拜耳布局NAMPT抑制剂新型ADC平台，Seagen也曾“撒网”

前言——NAMPT是个啥？NAMPT(Nicotinamide Phosphoribosyl Transferase，烟酰胺磷酸核糖转移酶)是NAD(Nicotinamide Adenine Dinucleotide，简称辅酶I)补救合成过程中的一个限速酶，它能催化烟酰胺（NAM）合成β-烟酰胺单核苷酸(NMN), NMN进而在NMNAT作用下转化为NAD。所以，NAM作为NAD的前体之一，在NAM转化为NAD的过程中，如果对NAMPT酶进行抑制，导致NAM无法合成NMN，最终导致NAD的合成受限。NAD是一种转递质子的辅酶，参与细胞物质代谢、能量合成、DNA修复等多项重要生理活动，维持足够的细胞内NAD含量对于所有细胞的存活至关重要，肿瘤患者体内细胞内与细胞外NAMPT均比正常对照有明显升高。 2018年Seagen探索了NAMPT抑制剂作为payload的可能性，相关结果发表在2018年的AACR会议上。近期，拜耳科学家在Bioconjugate Chemistry期刊上也发表了利用NAMPT抑制剂作为payload的研究文章。本篇我们主要以拜耳的这篇paper为主线对NAMPT抑制剂的payload平台做以解析，另外用Seagen的数据作为补充。01 先初步设计3种不同的liner-payload看看效果首先设计了EC1-EC3 3个linker-payload,母核结构如下：具体的结构如下图，linker接头均采用马来酰亚胺的接头，linker和payload之间我自己用红色的线给隔开，其中EC1和EC2为不可裂解linker；EC3采用的为mc-VA的酶切型linker，payload和EC1一样。接下来同时在C4.4a、HER2、B7H3 3个靶点上进行了开发。细胞活性上：payload相同的情况下，可裂解的linker EC3细胞活性明显好于不可裂解的linker EC1。关于细胞活性，小编补充：ADC细胞杀伤活性的检测，文献大多采用CTG试剂盒进行检测，其原理是基于细胞内ATP的水平；其实检测细胞活性的方法非常多，基于的原理也千差万别，拜耳的检测也是用的CTG的试剂盒，但Seagen在2018年的文献中提过，该方法做出的ADC的in vitro体外活性数值和in vivo动物药效并不完全一致，反而是以NAD水平的检测方法与in vivo动物药效对应关系更好。拜耳的科学家在此步检测时用的基于ATP水平的CTG检测法，但在单独筛选payload和后续优化ADC后也均采用两种指标同时作为检测手段，这提示研发人员一定要深刻的理解自己所研究药物发挥作用的机制，从而开发适合自己的活性assay，准确可靠的体外活性assay往往能事半功倍。02 基于药代进一步优化liner-payload 对EC3偶联的ADC进行了药代分析，发现除了本身的毒素Compound4外，还存在完整的linker-payload p-14,以及衍生出来的其他磷酸化产物。于是，接着优化第一步：更改linker,避免毒素部分过早的从抗体上发生解离。因为环状的MC接头在体内容易被带有巯基的抗体或者蛋白取代（发生交换反应），改成带负电的线性succinic amide接头后则不再与其他巯基交换，理论上药代上性质会更稳定，于是产生了EC4；第二步：降低代谢物旁观效应，扩大安全窗口。在EC4的基础上，payload上增加了一个喹啉基团，同时辅以PEG链增加水溶性帮助获得更高DAR值，产生了EC5。细胞活性上看，不管是单独的payload还是偶联成ADC后，EC5并没有取得意想中的效果，于是后续用EC4偶联的ADC进行体内药效评价。值得一提的是，EC4偶联的B7-H3-EC4，细胞活性的IC50可达低至7pM的水平，而HER2-EC4的IC50更是在0.3pM以下。03 in vivo动物药效 B7H3 ADC（DAR=7.8）治疗组，5 mg/kg剂量下, 7day一次，给药3次，7只小鼠中6只肿瘤完全消失，1只肿瘤缩小。此外，动物的体重也稳步上升，提示较好的安全性。HER2 ADC（10 mg/kg剂量下, 7day一次，共给药7次），治疗后7只小鼠肿瘤全部缩小（T/C=0.13），且停止治疗后肿瘤没有重新生长。C4.4a治疗组（10 mg/kg剂量下, 7day一次，共给药7次），8只小鼠中3只小鼠肿瘤缩小，5只小鼠疾病稳定（SD）。另外，该两组动物体重均有不同程度的下降，这个跟给药剂量和给药次数过多可能有关系，但同时也表明存在潜在的有效性风险。小编补充：MDA-MB-453细胞系是同时表达HER2和C4.4a的，HER2的表达量为C4.4a的4倍（80,000 antigen/cell VS 20,000 antigen/cell ）,此处也能看出，抗原表达量更高时，药效确实会更好。04 NAMPT抑制剂开发状况目前针对NAMPT抑制剂已有两款小分子处在临床阶段，padnarsertib（KPT-9274，由Karyopharm Therapeutics Inc开发，国内徳琪医药合作开发，目前处于临床II期）；OT-82（由OncoTartis Inc开发，目前处于临床I期）。而在此之前也曾有过针对NAMPT抑制剂开发的尝试，比如由Apoxis 开发的daporinad（APO-866）在细胞活性上IC50上可达1nM，但后来在连续三项分别针对B细胞慢性淋巴细胞白血病 (B-CLL) 、皮肤T细胞淋巴瘤(CTCL)、黑色素瘤的临床中均折戟沉沙。nM这个水平的细胞活性，单独用作化药治疗会因为毒性太强导致安全窗口过窄而做不出有效性，但作为ADC payload来用的话或许是大有空间的。另外，关于NAMPT抑制剂，此处我能想到的一个潜在风险是，抑制了NAD的补救合成途径后，其他旁路途径是否还可以作为补充，以及补充的效果如何仍待仔细研究一下，具体临床效果怎么样，还需期待拜耳的后续。参考文献[1] Sampath, Deepak, Misner, et al. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer, 2015.[2] Valentina, Audrito, Antonella, et al. Targeting metabolic reprogramming in metastatic melanoma: the key role of nicotinamide phosphoribosyltransferase (NAMPT), 2019.[3] Niels Böhnke, Markus Berger, Nils Griebenow, et al. A Novel NAMPT Inhibitor-Based Antibody− Drug Conjugate Payload Class for Cancer Therapy, 2022. （拜耳paper）[4] Neumann C S , Olivas K C ,Anderson M E , et al. Targeted Delivery of Cytotoxic NAMPT Inhibitors Using Antibody-Drug Conjugates, 2018. （Seagen paper）识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

小分子药物免疫疗法AACR会议合作抗体药物偶联物抗体

100 项与 OT-82 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
B细胞淋巴瘤	临床1期	美国	Oncotartis, Inc.	2019-07-29
滤泡性淋巴瘤	临床1期	美国	Oncotartis, Inc.	2019-07-29
霍奇金淋巴瘤	临床1期	美国	Oncotartis, Inc.	2019-07-29
外周T细胞淋巴瘤	临床1期	美国	Oncotartis, Inc.	2019-07-29
血液肿瘤	临床前	俄罗斯	OncoTartis LLC	-