Abstract
Abstract We have isolated and characterized blast cells and leukemic stem cells (LSCs) enriched from AML patients and identified cell surface targets selectively expressed on AML blast cells and LSCs and not their normal hematopoietic stem cell counterparts. A series of potent, specific, monoclonal antibodies (mAbs) have been generated against one of these AML LSC targets, IL1RAP. IL1RAP mAb clones were characterized for patient binding properties and also evaluated in in vitro cell based assays and in in vivo tumor xenograft models. These monoclonal antibodies demonstrated promising binding profiles in primary AML patients’ samples and robust anti-tumor activity in in vitro cell based assays and in vivo tumor xenograft models. Specifically, select clones have a high degree of specific binding to AML primary patient samples (>90%), and specifically kill primary patient AML cells in complement-dependent cytotoxicity assays. These IL1RAP clones are being evaluated for inhibition of clonogenic potential of AML patient samples in vitro in colony forming assays and against normal clonogenic hematopoietic bone marrow derived stem cells. Select IL1RAP mAb clones evaluated in orthotopic AML tumor xenograft models have shown potent inhibition of tumor engraftment as well as significant tumor growth inhibition effects ranging from 80-90%. Because a key driver of LSC resistance is their quiescence, we also evaluated the antitumor effect of IL1RAP mAbs on quiescent AML cells in vitro. In summary, the patient binding profiles and in vitro and in vivo efficacy against AML cells indicates that targeting IL1RAP is a promising therapeutic approach for the treatment of AML and has the potential for effective eradication of AML LSCs and long term remission in the clinic. Citation Format: Ping Jiang, Sharmili Roy, Jen Huang, Trang Dao-Pick, Jennifer Lu, Madhavi Mishra, Jeffrey Lin, Eric D. Hsi, Robert J. Tressler, Holger Karsunky. Generation and characterization of antibodies specific for IL1RAP antigen to target quiescent and proliferating AML leukemic stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 662. doi:10.1158/1538-7445.AM2014-662
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