Abstract 5671: AFM26 - A novel CD16A-directed bispecific TandAb targeting BCMA for multiple myeloma
Authors: Gantke Thorsten , Reusch Uwe , Ellwanger Kristina , Fucek Ivica , Weichel Michael , Treder Martin 
Published: July 2017

Abstract
Multiple myeloma (MM) is the second most common haematological cancer and is characterized by the accumulation of neoplastic plasma cells in the bone marrow and production of high levels of monoclonal immunoglobulin (M-protein). While historically considered incurable, recent approvals and ongoing clinical trials with monoclonal antibodies (mAbs) targeting surface antigens promise greatly improved outcomes and have heralded a new era of MM treatment in which immunotherapies are expected to take center stage. However, an unmet need remains as patients eventually relapse and/or become refractory to currently available treatments. Consequently, novel immunotherapeutic approaches are needed to provide improved treatment options to MM patients. Among the currently explored targets, B-cell maturation antigen (BCMA, CD269) is considered to be particularly attractive due to its limited expression on healthy tissues and almost universal expression on myeloma cells in the majority of patients.
Natural killer (NK) cells are cytotoxic effectors of the innate immune system capable of rapidly eradicating infected and transformed cells. The cytolytic activity of NK-cells can be used therapeutically to induce tumor cell lysis by direct engagement of the activating receptor CD16A (FcγRIIIa) using mAbs (ADCC). Despite similar mechanisms of target cell lysis, activation of NK-cells is not associated with the systemic symptoms of high level cytokine release as seen with direct T-cell engagement. Hence, it is considered a potent immunotherapeutic approach with reduced toxicity and a well-manageable safety profile. NK-cells readily infiltrate bone marrow and are thought to contribute to the efficacy of current myeloma treatments. Therefore, redirecting NK-cell cytotoxicity to malignant plasma cells appears to be a suitable therapeutic approach for MM.
Here we describe the characterization of AFM26, a novel tetravalent bispecific tandem diabody (TandAb) that specifically targets BCMA and CD16A with high affinity and induces potent and efficacious myeloma cell lysis. AFM26 incorporates an affinity-improved anti-CD16A domain and interacts bivalently with NK-cells, resulting in high avidity and prolonged cell surface retention that is largely unaffected by the presence of polyclonal IgG. Notably, AFM26 potently induces NK-cell-mediated in vitro lysis of target cells expressing low levels of BCMA at low effector:target ratios, even in presence of polyclonal IgG. This may suggest that AFM26, in contrast to classical mAbs, retains ADCC activity at low antibody concentrations in presence of serum IgG and despite high levels of IgG M-protein occurring in about half of MM patients. AFM26 exhibits high protein stability, full cross-reactivity with cynomolgus antigens (BCMA and CD16A) and does not bind APRIL and TACI, two functionally related receptors. These data suggest that TandAb AFM26 is a promising and highly potent drug candidate for MM treatment.
Citation Format: Thorsten Gantke, Uwe Reusch, Kristina Ellwanger, Ivica Fucek, Michael Weichel, Martin Treder. AFM26 - A novel CD16A-directed bispecific TandAb targeting BCMA for multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5671. doi:10.1158/1538-7445.AM2017-5671