Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia

• Type of Material: Article
• Authors: Bhavani Gopalakrishnan, Ohio State University; Carolyn Cheney, Ohio State University; Rajeswaran Mani, Ohio State University; Xiaokui Mo, Ohio State University; Donna Bucci, Ohio State University; Alison Walker, Ohio State University; Rebecca Klisovic, Emory University; Bhavana Bhatnagar, Ohio State University; Katherine Walsh, Ohio State University; Bjoern Rueter, Boehringer Ingelheim Pharma GmbH, Biberach/Riss; Irene C. Waizenegger, Boehringer Ingelheim Pharma GmbH, Biberach/Riss; Karl-Heinz Heider, Boehringer Ingelheim Pharma GmbH, Biberach/Riss; William Blum, Emory University; Sumithira Vasu, Ohio State University; Natarajan Muthusamy, Ohio State University
• Language: English
• Date: 2018-01-01
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © Gopalakrishnan et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.23880
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 9
• Issue: 11
• Start Page: 9706
• End Page: 9713
• Grant/Funding Information: We gratefully acknowledge specimens provided by the OSUCCC Leukemia Tissue Bank, which is funded in part by NIH Contract P30CA016058
• Keywords: CD33; NK cells; volasertib; BI 836858; AML
• Research Categories: Health Sciences, Oncology

Abstract

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.