Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia
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Bhavani Gopalakrishnan1, Carolyn Cheney1, Rajeswaran Mani1, Xiaokui Mo1,2, Donna Bucci1, Alison Walker3, Rebecca Klisovic4, Bhavana Bhatnagar3, Katherine Walsh3, Bjoern Rueter5, Irene C. Waizenegger6, Karl-Heinz Heider6, William Blum4, Sumithira Vasu1,3,* and Natarajan Muthusamy1,3,*
1Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
2Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA
3Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
4Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
5Boehringer Ingelheim Pharma GmbH, Biberach/Riss, Germany
6Boehringer Ingelheim RCV, Vienna, Austria
*These authors contributed equally to this work
Sumithira Vasu, email: [email protected]
Natarajan Muthusamy, email: [email protected]
Keywords: AML; BI 836858; volasertib; NK cells; CD33
Received: December 01, 2016 Accepted: November 11, 2017 Published: January 03, 2018
Acute myeloid leukemia (AML) is the second most common type of leukemia in adults. Incidence of AML increases with age with a peak incidence at 67 years. Patients older than 60 years have an unfavorable prognosis due to resistance to conventional chemotherapy. Volasertib (BI 6727) is a cell-cycle regulator targeting polo-like kinase which has been evaluated in clinical trials in AML. We evaluated effects of volasertib in primary patient samples and NK cells. At equivalent doses, volasertib is cytotoxic to AML blasts but largely spares healthy NK cells. We then evaluated the effect of volasertib treatment in combination with BI 836858 on primary AML blast samples using antibody-dependent cellular cytotoxicity (ADCC) assays. Volasertib treatment of NK cells did not impair NK function as evidenced by comparable levels of BI 836858 mediated ADCC in both volasertib-treated and control-treated NK cells. In summary, volasertib is cytotoxic to AML blasts while sparing NK cell viability and function. Higher BI 836858 mediated ADCC was observed in patient samples pretreated with volasertib. These findings provide a strong rationale to test combination of BI 836858 and volasertib in AML.
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