Targeting mutant NPM1-expressing AML with T cell receptor-like antibodies.

IF 4.5 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2026-09-30 eCollection Date: 2026-10-16 DOI:10.1016/j.isci.2026.117630

Yunda Hong, Dabing Chen, Jingjing Xu, Yanxin Chen, Yang Shi, Zikang Wang, Congling Gan, Zihan Wang, Qian Li, Jiahua Gao, Huilin Guo, Ningshao Xia, Yangtao Wu, Tianying Zhang, Quan Yuan, Ting Yang, Jianda Hu

{"title":"Targeting mutant NPM1-expressing AML with T cell receptor-like antibodies.","authors":"Yunda Hong, Dabing Chen, Jingjing Xu, Yanxin Chen, Yang Shi, Zikang Wang, Congling Gan, Zihan Wang, Qian Li, Jiahua Gao, Huilin Guo, Ningshao Xia, Yangtao Wu, Tianying Zhang, Quan Yuan, Ting Yang, Jianda Hu","doi":"10.1016/j.isci.2026.117630","DOIUrl":null,"url":null,"abstract":"This study developed T cell receptor (TCR)-like antibodies targeting the intracellular neoantigen derived from the common NPM1 type A mutation (NPM1mutA) in acute myeloid leukemia (AML), presented by HLA-A∗02:01. Hybridoma technology was employed to generate a murine monoclonal antibody (m2E2) specifically recognizing the NPM1mutA 283-291-HLA-A∗02:01 complex. The lead antibody was humanized (hu2E2) and engineered into bispecific formats engaging CD3 or CD16, alongside an Fc-enhanced variant (hu2E2-GAALIE). In vitro, these antibodies mediated potent antibody-dependent cellular cytotoxicity (ADCC) against NPM1mutA-positive AML cell lines, inducing apoptosis and cytokine release. In vivo, a single dose of hu2E2 variants significantly suppressed tumor growth in NCG mice engrafted with OCI-AML3-LUC cells. Fc silencing abolished antitumor efficacy, confirming FcγR-dependent mechanisms. Critically, m2E2 specifically bound to primary CD33+ blasts from HLA-A∗02:01-positive, NPM1-mutated AML patients. These findings demonstrate a potent immunotherapeutic strategy for targeting intracellular oncogenic peptides in AML and support further clinical development of TCR-like antibodies.","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 10","pages":"117630"},"PeriodicalIF":4.5000,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657108/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"iScience","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1016/j.isci.2026.117630","RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/10/16 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

This study developed T cell receptor (TCR)-like antibodies targeting the intracellular neoantigen derived from the common NPM1 type A mutation (NPM1^mutA) in acute myeloid leukemia (AML), presented by HLA-A∗02:01. Hybridoma technology was employed to generate a murine monoclonal antibody (m2E2) specifically recognizing the NPM1^mutA _283-291-HLA-A∗02:01 complex. The lead antibody was humanized (hu2E2) and engineered into bispecific formats engaging CD3 or CD16, alongside an Fc-enhanced variant (hu2E2-GAALIE). In vitro, these antibodies mediated potent antibody-dependent cellular cytotoxicity (ADCC) against NPM1^mutA-positive AML cell lines, inducing apoptosis and cytokine release. In vivo, a single dose of hu2E2 variants significantly suppressed tumor growth in NCG mice engrafted with OCI-AML3-LUC cells. Fc silencing abolished antitumor efficacy, confirming FcγR-dependent mechanisms. Critically, m2E2 specifically bound to primary CD33⁺ blasts from HLA-A∗02:01-positive, NPM1-mutated AML patients. These findings demonstrate a potent immunotherapeutic strategy for targeting intracellular oncogenic peptides in AML and support further clinical development of TCR-like antibodies.

查看原文本刊更多论文

用T细胞受体样抗体靶向表达npm1的AML突变体。

这项研究开发了T细胞受体（TCR）样抗体，靶向急性髓性白血病（AML）中常见的NPM1 A型突变（NPM1mutA）衍生的细胞内新抗原，HLA-A∗02:01。利用杂交瘤技术产生特异性识别NPM1mutA 283-291-HLA-A∗02:01复合体的小鼠单克隆抗体（m2E2）。该先导抗体被人源化（hu2E2），并被设计成双特异性的形式，与CD3或CD16结合，以及fc增强变体（hu2E2- gaalie）。在体外，这些抗体介导了针对npm1muta阳性AML细胞系的强效抗体依赖性细胞毒性（ADCC），诱导细胞凋亡和细胞因子释放。在体内，单剂量的hu2E2变体显著抑制了OCI-AML3-LUC细胞移植的NCG小鼠的肿瘤生长。Fc沉默消除了抗肿瘤效果，证实了Fcγ r依赖机制。关键的是，m2E2特异性结合HLA-A∗02:01阳性，npm1突变的AML患者的原代CD33+胚。这些发现证明了一种有效的针对AML细胞内致癌肽的免疫治疗策略，并支持tcr样抗体的进一步临床开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

期刊介绍： Science has many big remaining questions. To address them, we will need to work collaboratively and across disciplines. The goal of iScience is to help fuel that type of interdisciplinary thinking. iScience is a new open-access journal from Cell Press that provides a platform for original research in the life, physical, and earth sciences. The primary criterion for publication in iScience is a significant contribution to a relevant field combined with robust results and underlying methodology. The advances appearing in iScience include both fundamental and applied investigations across this interdisciplinary range of topic areas. To support transparency in scientific investigation, we are happy to consider replication studies and papers that describe negative results. We know you want your work to be published quickly and to be widely visible within your community and beyond. With the strong international reputation of Cell Press behind it, publication in iScience will help your work garner the attention and recognition it merits. Like all Cell Press journals, iScience prioritizes rapid publication. Our editorial team pays special attention to high-quality author service and to efficient, clear-cut decisions based on the information available within the manuscript. iScience taps into the expertise across Cell Press journals and selected partners to inform our editorial decisions and help publish your science in a timely and seamless way.