PO.ET01.05 · 实验与分子治疗
搭载拓扑异构酶I抑制剂载荷的CD180靶向ADC在AML肿瘤中实现强效疗效
CD180-targeting ADCs with a topoisomerase I inhibitor payload achieve strong efficacy in AML tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
CD180(RP105)是一种I型单次跨膜蛋白,可与MD-1或MD-2形成异二聚体以实现稳定的表面表达。CD180被表征为一种孤儿Toll样受体,主要表达于成熟B细胞、树突状细胞和巨噬细胞,在多种血液系统恶性肿瘤中也上调,包括弥漫性大B细胞淋巴瘤、套细胞淋巴瘤和急性髓系白血病(AML)。在此,我们将CD180确定为AML的一个新颖且有前景的治疗靶点,并描述了一种CD180靶向抗体-药物偶联物(ADC)的开发及其生化特性、跨AML模型的抗肿瘤活性,以及在非人灵长类动物中的药代动力学和安全性特征。与新兴数据集一致,我们在一大批原发性AML样本中观察到AML原始细胞(包括白血病干细胞和祖细胞群)上CD180的高度、均一表达,而在健康造血干细胞、常见髓系祖细胞或正常组织上表达极少或无表达。我们生成了一种全人源单克隆抗体,可高亲和力、选择性结合人和食蟹猴CD180/MD-1复合物,且与啮齿类CD180无反应性。该抗体以8的药物抗体比(DAR)偶联至一种拓扑异构酶I抑制剂,该载荷因其在血液系统恶性肿瘤中的效力和良好稳定性特征而被选用。该ADC表现出快速内化、对CD180表达细胞的高特异性,以及在AML细胞系、原代离体样本和患者来源异种移植模型中的强效细胞毒性,治疗应答与CD180表达水平密切相关。在食蟹猴中开展的探索性毒性研究(10、30和60 mg/kg)中,该ADC耐受性良好,在任何剂量下均未观察到靶点相关毒性或血细胞减少。所有临床和组织病理学发现均为轻度且可逆,确定最大耐受剂量为60 mg/kg。该ADC还展现出优异的理化稳定性和可开发性特征。综上,这些发现支持将CD180靶向ADC疗法推进至针对CD180阳性AML患者的临床开发。
查看英文原文 English abstract
CD180 (RP105) is a type I single-pass transmembrane protein that heterodimerizes with MD-1 or MD-2 to enable stable surface expression. Characterized as an orphan Toll-like receptor predominantly expressed on mature B cells, dendritic cells, and macrophages, CD180 is also upregulated in multiple hematologic malignancies, including diffuse large B-cell lymphoma, mantle cell lymphoma, and acute myeloid leukemia (AML). Here, we identify CD180 as a novel and promising therapeutic target for AML and describe the development of a CD180-directed antibody-drug conjugate (ADC) along with its biochemical properties, antitumor activity across AML models, and pharmacokinetic and safety characteristics in non-human primates.Consistent with emerging datasets, we observed high, homogeneous CD180 expression on AML blasts, including leukemic stem and progenitor compartments, across a large cohort of primary AML specimens, with minimal to no expression on healthy hematopoietic stem cells, common myeloid progenitors, or normal tissues. We generated a fully human monoclonal antibody with high-affinity, selective binding to the human and cynomolgus CD180/MD-1 complex and no reactivity to rodent CD180.This antibody was conjugated to a topoisomerase I inhibitor with a drug-to-antibody ratio (DAR) of 8, selected for its potency and favorable stability profile in hematologic malignancies. The ADC demonstrated rapid internalization, high specificity for CD180-expressing cells, and potent cytotoxicity in AML cell lines, primary ex vivo samples, and patient-derived xenograft models, with therapeutic response strongly correlating with CD180 expression levels.In an exploratory toxicity study in cynomolgus monkeys (10, 30, and 60 mg/kg), the ADC was well tolerated, with no target-related toxicities or cytopenias observed at any dose. All clinical and histopathological findings were mild and reversible, establishing a maximum tolerated dose of 60 mg/kg. The ADC also demonstrated excellent physicochemical stability and developability properties.Together, these findings support advancement of CD180-targeted ADC therapy into clinical development for patients with CD180-positive AML.
利益披露 Disclosure
G. Kaushik,
Corellia AI Employment.
M. Bell,
Corellia AI Employment.
A. Mondal,
Corellia AI Employment.
M. Hilbert,
Corellia AI Employment.
A. Mukharjee, None.
M. Ritchie,
Corellia AI Employment.
K. Komurov,
Corellia AI Employment.