IL3RA-Targeting Antibody-Drug Conjugate BAY-943 with a Kinesin Spindle Protein Inhibitor Payload Shows Efficacy in Preclinical Models of Hematologic Malignancies.

Dennis Kirchhoff,Hans-Georg Lerchen,Christoph Mahlert,Pascale Buchmann,Michael Erkelenz,Dominik Mumberg,Lisa Dietz,Sandra Johanssen,Simone Greven,Antje Margret Wengner,Anette Sommer,Oliver Von Ahsen,Ruprecht Zierz,Stephan Märsch,Beatrix Stelte-Ludwig

doi:10.3390/cancers12113464

Abstract

Simple SummaryIL3RA (alpha subunit of the interleukin 3 receptor) is a cell membrane protein frequently expressed in acute myeloid leukemia (AML) and Hodgkin lymphoma; therefore, it is a promising therapeutic target for cancer treatment. Here, we introduce BAY-943, a novel IL3RA-targeting antibody–drug conjugate that shows potent and selective efficacy in IL3RA-positive AML and Hodgkin lymphoma cell lines. In IL3RA-positive AML mouse models, BAY-943 improved survival and reduced tumor burden. Impressively, treatment with BAY-943 induced complete tumor remission in 12 out of 13 mice in an IL3RA-positive HL model. BAY-943 showed a favorable safety profile without any signs of toxicity in rats and monkeys. Overall, these preclinical results support the further development of BAY-943 for the treatment of IL3RA-positive hematologic malignancies.IL3RA (CD123) is the alpha subunit of the interleukin 3 (IL-3) receptor, which regulates the proliferation, survival, and differentiation of hematopoietic cells. IL3RA is frequently expressed in acute myeloid leukemia (AML) and classical Hodgkin lymphoma (HL), presenting an opportunity to treat AML and HL with an IL3RA-directed antibody–drug conjugate (ADC). Here, we describe BAY-943 (IL3RA-ADC), a novel IL3RA-targeting ADC consisting of a humanized anti-IL3RA antibody conjugated to a potent proprietary kinesin spindle protein inhibitor (KSPi). In vitro, IL3RA-ADC showed potent and selective antiproliferative efficacy in a panel of IL3RA-expressing AML and HL cell lines. In vivo, IL3RA-ADC improved survival and reduced tumor burden in IL3RA-positive human AML cell line-derived (MOLM-13 and MV-4-11) as well as in patient-derived xenograft (PDX) models (AM7577 and AML11655) in mice. Furthermore, IL3RA-ADC induced complete tumor remission in 12 out of 13 mice in an IL3RA-positive HL cell line-derived xenograft model (HDLM-2). IL3RA-ADC was well-tolerated and showed no signs of thrombocytopenia, neutropenia, or liver toxicity in rats, or in cynomolgus monkeys when dosed up to 20 mg/kg. Overall, the preclinical results support the further development of BAY-943 as an innovative approach for the treatment of IL3RA-positive hematologic malignancies.

Highlights

Interleukin 3 receptor subunit alpha (IL3RA; known as CD123) is the α subunit of the heterodimeric interleukin 3 (IL-3) receptor
IL3RA has been shown to be a very useful biomarker for the detection of minimal residual disease, thereby predicting relapse in acute myeloid leukemia (AML) patients [20,21]. These results suggest that IL3RA is a very attractive target for an antibody–drug conjugate (ADC)
BAY-943 to human and cynomolgus monkey IL3RA was assessed by surface plasmon resonance (SPR) and flow cytometry

Summary

Introduction

Interleukin 3 receptor subunit alpha (IL3RA; known as CD123) is the α subunit of the heterodimeric IL-3 receptor. Together with the β subunit, it forms a functional high-affinity receptor for IL-3 [1,2,3]. IL-3 is a pleiotropic cytokine that is mainly produced by activated T lymphocytes, and it regulates the function and production of hematopoietic and immune cells [4]. IL3RA is expressed at high levels in ≈80% of acute myeloid leukemias (AML) [1,2,5], 59–100% of classical Hodgkin lymphomas (cHL), and the majority of blastic plasmacytoid dendritic cell neoplasms (BPDCN) [6,7,8,9,10]. IL3RA overexpression on AML blasts has been associated with an increased number of leukemic blast cells at diagnosis and with a negative prognosis [15]

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