Braciak Todd A, Roskopf Claudia C, Wildenhain Sarah, Fenn Nadja C, Schiller Christian B, Schubert Ingo A, Jacob Uwe, Honegger Annemarie, Krupka Christina, Subklewe Marion, Spiekermann Karsten, Hopfner Karl-Peter, Fey Georg H, Aigner Michael, Krause Stefan, Mackensen Andreas, Oduncu Fuat S
Department of Hematology and Oncology, Medizinische Klinik und Poliklinik III, Klinikum der Universität München, Munich, Germany.
Department of Biochemistry and Gene Center, Ludwig-Maximilians-Universität, Munich, Germany.
Oncoimmunology. 2018 Jul 30;7(9):e1472195. doi: 10.1080/2162402X.2018.1472195. eCollection 2018.
A number of agents designed for immunotherapy of Acute Myeloid Leukemia (AML) are in preclinical and early clinical development. Most of them target a single antigen on the surface of AML cells. Here we describe the development and key biological properties of a tri-specific agent, the dual-targeting triplebody SPM-2, with binding sites for target antigens CD33 and CD123, and for CD16 to engage NK cells as cytolytic effectors. Primary blasts of nearly all AML patients carry at least one of these target antigens and the pair is particularly promising for the elimination of blasts and leukemia stem cells (LSCs) from a majority of AML patients by dual-targeting agents. The cytolytic activity of NK cells mediated by SPM-2 was analyzed for primary leukemic cells from 29 patients with a broad range of AML-subtypes. Blasts from all 29 patients, including patients with genomic alterations associated with an unfavorable genetic subtype, were lysed at nanomolar concentrations of SPM-2. Maximum susceptibility was observed for cells with a combined density of CD33 and CD123 above 10,000 copies/cell. Cell populations enriched for AML-LSCs (CD34pos and CD34pos CD38neg cells) from 2 AML patients carried an increased combined antigen density and were lysed at correspondingly lower concentrations of SPM-2 than unsorted blasts. These initial findings raise the expectation that SPM-2 may also be capable of eliminating AML-LSCs and thus of prolonging survival. In the future, patients with a broad range of AML subtypes may benefit from treatment with SPM-2.
一些设计用于急性髓系白血病（AML）免疫治疗的药物正处于临床前和早期临床开发阶段。其中大多数靶向AML细胞表面的单一抗原。在此，我们描述了一种三特异性药物——双靶向三体SPM-2的开发及其关键生物学特性，它具有针对靶抗原CD33和CD123以及CD16的结合位点，可使自然杀伤（NK）细胞作为溶细胞效应器发挥作用。几乎所有AML患者的原始细胞都携带这些靶抗原中的至少一种，并且这一对抗原对于通过双靶向药物消除大多数AML患者的原始细胞和白血病干细胞（LSC）特别有前景。我们分析了SPM-2介导的NK细胞对29例具有广泛AML亚型的患者的原发性白血病细胞的溶细胞活性。包括具有与不良遗传亚型相关的基因组改变的患者在内的所有29例患者的原始细胞，在纳摩尔浓度的SPM-2作用下均被裂解。对于CD33和CD123组合密度高于10,000拷贝/细胞的细胞，观察到最大敏感性。来自2例AML患者的富集AML-LSC（CD34阳性和CD34阳性CD38阴性细胞）的细胞群体具有更高的组合抗原密度，并且与未分选的原始细胞相比，在相应更低浓度的SPM-2作用下被裂解。这些初步发现引发了人们的期望，即SPM-2可能也能够消除AML-LSC，从而延长生存期。未来，广泛AML亚型的患者可能会从SPM-2治疗中受益。
