Year: 2024
Type: article
Abstract: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML. Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples. IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAP high AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAP high MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002). The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.
Source: Journal of Hematology & Oncology
Authors: Yi Zhang, Miso Park, Lucy Y. Ghoda, Dandan Zhao, Melissa Valerio, Ebtesam Nafie, Asaul Gonzalez, Kevin Ly, Bea Parcutela, Hyeran Choi, Xubo Gong, Fang Chen, Kaito Harada, Zhenhua Chen, Le Xuan Truong Nguyen, Flavia Pichiorri, Jianjun Chen, Joo Song, Stephen J. Forman, Idoroenyi Amanam, Bin Zhang, Jie Jin, John C. Williams, Guido Marcucci
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,690
Awards: Vascular Remodeling in the Bone Marrow Leukemic Niche: A Therapeutic Target?, The role and mechanism of FTO in leukemogenesis and drug response, G553281296, Targeting FTO to treat acute myeloid leukemia, The role and mechanism of METTL3/METTL14-mediated RNA modification in the pathogenesis and drug-resistance of AML, G8903589889, The Role of miR-142 in the Transformation of Clonal Hematopoietic Disorders into AML, TET2-mediated epitranscriptomic regulation in leukemia microenvironment, Cancer Center Support Grant, Targeting Immune Escape in CML/MPN Transformation, The role and therapeutic potential of IGF2BP2 in MLL-rearranged leukemia
OpenAlex ID: W4401565874