Targeting CD157 in AML using a novel, Fc-engineered antibody construct

// Christina Krupka 1, 2, 3 , Felix S. Lichtenegger 1, 2, 3 , Thomas Kohnke 1, 2, 3 , Jan Bogeholz 4 , Veit Bucklein 1, 2, 3 , Michael Roiss 1, 2, 3 , Torben Altmann 1, 2, 3 , To Uyen Do 5 , Rachel Dusek 5 , Keith Wilson 5, * , Arnima Bisht 5 , Jon Terrett 6, * , Dee Aud 6, * , Esteban Pombo-Villar 5, * , Christian Rohlff 5 , Wolfgang Hiddemann 1 , Marion Subklewe 1, 2, 3 1 Department of Internal Medicine III, Klinikum of The LMU Munich, Munich, Germany 2 Clinical Cooperation Group Immunotherapy at The Helmholtz Institute Munich, Munich, Germany 3 Laboratory of Translational Cancer Immunology, Gene Center Munich, Ludwig-Maximilians-University, Munich, Germany 4 Department of Hematology, University Hospital Zurich, Zurich, Switzerland 5 Independent consultant Oxford BioTherapeutics Ltd, Abingdon, United Kingdom and San Jose, CA, USA 6 CRISPR Therapeutics, Cambridge, MA, USA * Were employed at Oxford Biotherapeutics at the time the data was generated Correspondence to: Subklewe Marion, email: Marion.Subklewe@med.uni-muenchen.de Keywords: AML, Immunotherapy, CD157, Antibody, Fc-engineering Received: November 01, 2016      Accepted: February 27, 2017      Published: March 09, 2017 ABSTRACT Antibody-based immunotherapy represents a promising strategy to eliminate chemorefractory leukemic cells in acute myeloid leukemia (AML). In this study, we evaluated a novel Fc-engineered antibody against CD157 (MEN1112) for its suitability as immunotherapy in AML. CD157 was expressed in 97% of primary AML patient samples. A significant, albeit lower expression level of CD157 was observed within the compartment of leukemia-initiating cells, which are supposed to be the major source of relapse. In healthy donor bone marrow, CD157 was expressed on CD34 + cells. In ex vivo assays, MEN1112 triggered natural killer (NK) cell-mediated cytotoxicity against AML cell lines and primary AML cells. Compared to its parental analogue, the Fc-engineered antibody exhibited higher antibody dependent cellular cytotoxicity responses. Using NK cells from AML patients, we observed heterogeneous MEN1112-mediated cytotoxicity against AML cells, most likely due to well-documented defects in AML-NK cells and corresponding inter-patient variations in NK cell function. Cytotoxicity could not be correlated to the time after completion of chemotherapy. In summary, we could demonstrate that CD157 is strongly expressed in AML. MEN1112 is a promising antibody construct that showed high cytotoxicity against AML cells and warrants further clinical testing. Due to variability in NK-cell function of AML patients, the time of application during the course of the disease as well as combinatorial strategies might influence treatment results.