PNT001 是一种识别顺式-pT231 tau 的抗体，本文介绍了其临床前特征和 IND 申报前安全性研究。

Preclinical characterization and IND-enabling safety studies for PNT001, an antibody that recognizes cis-pT231 tau.

机构信息

Pinteon Therapeutics, Inc., Discovery Biology, Newton, Massachusetts, USA.

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

出版信息

Alzheimers Dement. 2023 Oct;19(10):4662-4674. doi: 10.1002/alz.13028. Epub 2023 Apr 1.

DOI:10.1002/alz.13028

PMID:37002928

Abstract

BACKGROUND

The cis-conformer of tau phosphorylated at threonine-231 (cis-pT231 tau) is hypothesized to contribute to tauopathies. PNT001 is a humanized, monoclonal antibody that recognizes cis-pT231 tau. PNT001 was characterized to assess clinical development readiness.

METHODS

Affinity and selectivity were assessed by surface plasmon resonance and enzyme-linked immunosorbent assay. Immunohistochemistry (IHC) was performed with brain sections from human tauopathy patients and controls. Real-time quaking-induced conversion (RT-QuIC) was used to assess whether PNT001 reduced tau seeds from Tg4510 transgenic mouse brain. Murine PNT001 was evaluated in vivo in the Tg4510 mouse.

RESULTS

The affinity of PNT001 for a cis-pT231 peptide was 0.3 to 3 nM. IHC revealed neurofibrillary tangle-like structures in tauopathy patients with no detectable staining in controls. Incubation of Tg4510 brain homogenates with PNT001 lowered seeding in RT-QuIC. Multiple endpoints were improved in the Tg4510 mouse. No adverse findings attributable to PNT001 were detected in Good Laboratory Practice safety studies.

DISCUSSION

The data support clinical development of PNT001 in human tauopathies.

摘要

背景

tau 蛋白在苏氨酸-231 位磷酸化的顺式构象（cis-pT231 tau）被认为与 tau 病有关。PNT001 是一种人源化的单克隆抗体，可识别 cis-pT231 tau。对 PNT001 进行了表征，以评估其临床开发的准备情况。

方法

通过表面等离子体共振和酶联免疫吸附试验评估亲和力和选择性。用来自人类 tau 病患者和对照者的脑切片进行免疫组织化学（IHC）。使用实时震颤诱导转换（RT-QuIC）评估 PNT001 是否能减少 Tg4510 转基因小鼠脑内的 tau 种子。在 Tg4510 小鼠中进行了体内评估。

结果

PNT001 对 cis-pT231 肽的亲和力为 0.3 到 3 nM。IHC 显示在 tau 病患者中有神经原纤维缠结样结构，而在对照组中则没有检测到染色。用 PNT001 孵育 Tg4510 脑匀浆可降低 RT-QuIC 中的种子。在 Tg4510 小鼠中，多个终点得到改善。在良好实验室规范安全性研究中未发现与 PNT001 有关的不良发现。