Augmentation of CD38 Tumour-Targeting with immunostimulation

Multiple myeloma is a malignancy of plasma cells for which no cure is currently available. Thus, new therapeutic approaches are required. Monoclonial antibodies (mAbs) have demonstrated to be a good treatment option for multiple myeloma. CD38 is highly expressed on malignant plasma cells, and is a target for mAb therapy. During the last decades, several variants of CD38-targeting antibodies have been produced which mediate antibody-dependent cell-mediated cytotoxicity, complement dependent cytotoxicity or antibody-dependent cell-mediated phagocytes (ADCP) leading to the direct destruction of multiple myeloma tumour cells (Atanackovic et al., 2016).

The project will investigate whether CD38 mAbs' tumour-targeting ability can be enhanced in combination with CD27 mAbs. As shown in preclinical studies, agonistic CD27 mAbs can enhance the efficacy of tumour-targeting mAbs (Tural et al, 2017). The application of agonistic CD27 mAb monotherapy in several tumour mouse models resulted either in complete protection against the tumour (French et al., 2017) or led to a reduction in metastasis and tumour growth (Roberts et al., 2010; Sakanishi and Yagita, 2010). A more recent study by Turaj et al. (2017) treated multiple B-cell lymphoma mouse models with a combination of CD20- and CD27- targeting mAbs. The results demonstrated significant therapeutic benefit in combining the mAbs. Stimulation of CD27 resulted in increased ADCP activity by anti-CD20.

The project will be divided into three parts. First is the functional characterisation of a panel of human CD27 (hCD27) mAbs through in vitro immunological assays (e.g. activation of NFKB-GFP reporter cell line and T-cell proliferation assays). Second is the setting up of mouse models appropriate for CD38-targeting (and in combination with CD27 mAb), namely using the BCL1, A31 and 5T33 murine myeloma models. Finally, a nCD38 Tg model will be designed. Anti-hCCD38 will be tested in combination with anti-hCD27 and/or other immunostimulators, identified from earlier experiments in B-cell lines transfected with hCD38 (e.g. EL4, A20) in WT mice, or hCD27 Tg mice, in the case of anti-hCD27. The whole project aims to investigate the mechanisms of antibody combination therapies and produce pre-clinical data for subsequent clinical trials.