人IgG1 Fc融合CD38靶向双特异性抗体的新型环结构及其在急性髓系白血病中的抗肿瘤作用。

Novel loop structure of human IgG1 Fc fused CD38 targeted bispecific antibodies and their anti-tumor effect in acute myeloid leukemia.

作者信息

Wang Shisen, Chen Manling, Zhou Tong, Guo Chengcai, Yan Zhifeng, Xu Yingxi, Xing Haiyan, Tang Kejing, Tian Zheng, Rao Qing, Qiu Shaowei, Wang Ying, Gu Runxia, Wang Min, Wang Jianxiang

机构信息

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.

Tianjin Institutes of Health Science, Tianjin, 301617, China.

出版信息

J Transl Med. 2025 Jul 28;23(1):849. doi: 10.1186/s12967-025-06827-2.

DOI:10.1186/s12967-025-06827-2

PMID:40721809

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12306004/

Abstract

BACKGROUND

Acute myeloid leukemia (AML) still lacks an ideal immunotherapy target. CD38 serves as a potential therapeutic target for AML. Classical bispecific antibody (BsAb) requires continuous infusion due to small molecular size and short half-life.

METHODS

The anti-human CD38 single-chain variable fragment (scFv) and anti-human CD3 scFv were cloned to expression plasmids. ExpiCHO-S cells were transfected, and the anti-CD38/anti-CD3 bispecific antibody (38-3-BsAbs) in CHO supernatants was efficiently purified. The anti-AML efficacy of 38-3-BsAbs was evaluated in vitro and in vivo.

RESULTS

The novel loop structures of non-human IgG Fc fused and human IgG1 Fc fused anti-CD38/anti-CD3 BsAbs, 38-3-loop-BsAb and 38-3-loopFc-BsAb, were designed and produced. Both 38-3-loop-BsAb and 38-3-loopFc-BsAb showed excellent anti-AML effects at low concentrations in vitro. AML xenograft NOD-scid IL2gamma (NSG) mouse model was adopted to evaluate therapeutic effects of 38-3-BsAb. The anti-leukemic effect of 38-3-loopFc-BsAb was superior.

CONCLUSIONS

We report on new structures of 38-3 bispecific antibody and demonstrate their anti-tumor effect in the treatment of AML.

摘要

背景

急性髓系白血病（AML）仍缺乏理想的免疫治疗靶点。CD38是AML的一个潜在治疗靶点。传统双特异性抗体（BsAb）由于分子尺寸小、半衰期短，需要持续输注。

方法

将抗人CD38单链可变片段（scFv）和抗人CD3 scFv克隆到表达质粒中。转染ExpiCHO-S细胞，并高效纯化CHO上清液中的抗CD38/抗CD3双特异性抗体（38-3-BsAbs）。在体外和体内评估38-3-BsAbs的抗AML疗效。

结果

设计并制备了非人IgG Fc融合和人IgG1 Fc融合的抗CD38/抗CD3双特异性抗体38-3-loop-BsAb和38-3-loopFc-BsAb的新型环结构。38-3-loop-BsAb和38-3-loopFc-BsAb在体外低浓度下均显示出优异的抗AML效果。采用AML异种移植NOD-scid IL2γ（NSG）小鼠模型评估38-3-BsAb的治疗效果。38-3-loopFc-BsAb的抗白血病作用更强。