In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4828-4828
Abstract:
Despite recent progress in the treatment of AML, clinical outcomes have improved only minimally over the past three decades. Therefore, novel therapeutic agents with a high therapeutic window and a favorable tolerability profile are urgently needed to improve the therapeutic outcome for AML patients. IL3RA (CD123) is the alpha subunit of the interleukin 3 (IL-3) receptor which regulates proliferation, survival and differentiation of hematopoietic cells. IL3RA is expressed at high frequency, with ~84% of AML cases and 59% of classical Hodgkin lymphoma (cHL) cases being positive. IL3RA is expressed in AML blast and leukemic stem cells (LSCs) but not in hematopoietic stem cells (HSCs). In healthy individuals, the IL3RA expression is restricted to myeloid progenitor cells, plasmacytoid dendritic cells (pDCs), basophils and - at low levels - monocytes and B-lymphocyte subsets. This expression pattern suggests that IL3RA could be a clinically relevant target for an antibody-drug conjugate (ADC) approach in treatment of AML, cHL, and MDS. BAY-943 is a novel antibody-drug conjugate (ADC) consisting of a humanized internalizing anti-IL3RA IgG1 antibody (Ab, EC50 on IL3RA-positive tumor cells in flow cytometry: 2-5 nM) conjugated via lysine residues to a potent proprietary kinesin spindle protein inhibitor (KSPi). The kinesin spindle protein (KSP/Eg5/KIF11) is essential for the proper segregation of duplicated centrosomes during spindle formation in the G2/M phase of the cell cycle, as such it is only active in proliferating cells. In vitro, in a panel of IL3RA-positive AML and HL cell lines, BAY-943 showed potency in the nano- to subnanomolar range. In IL3RA-positive cell line derived (CDX) AML xenograft models (MOLM-13 and MV4-11) and patient-derived xenograft (PDX) models, BAY-943 dosed at 10 mg/kg given Q7Dx increased survival compared to vehicle treated mice. Tumor burden (percentage of human CD45 positive AML cells) was significantly reduced compared to vehicle treated mice. In the subcutaneous IL3RA-positive cHL CDX model HDLM-2, BAY-943 dosed at 5 and 10 mg/kg Q7Dx2 induced complete tumor remission in 12 out of 13 mice. In safety studies in Cynomolgus monkeys, BAY-943 (which is cross-reactive with Cynomolgus IL3RA), up to 20 mg/kg single or 10 mg/kg repeat (QWx3) dose were well tolerated with no signs of thrombocytopenia, neutropenia and no liver toxicity, i.e. adverse events observed with ADCs containing other payload classes. As expected, a transient reduction of IL3RA expressing cell types (basophils, pDCs) was observed. In summary, IL3RA-KSPi-ADC BAY-943 shows efficacy in IL3RA-positive AML and HL models and has a favorable safety profile in monkey repeat dose studies. Overall, the preclinical results support further development of BAY-943 as an innovative approach for the treatment of IL3RA-positive AML. Citation Format: Anette Sommer, Dennis Kirchhoff, Antje M. Wengner, Beatrix Stelte-Ludwig, Hans-Georg Lerchen, Anne-Sophie Rebstock, Oliver von Ahsen, Lisa Dietz, Pascale Buchmann, Sandra Johanssen, Dominik Mumberg, Bertolt Kreft. Anti-tumor activity of BAY-943, an anti-IL3RA ADC with a novel KSP inhibitor payload, in CDX and PDX AML models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4828.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2019-4828
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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