MOR202, a HuCAL-derived fully human anti-CD38 antibody has proven to be highly effective in preclinical models of multiple myeloma (MM) and is currently evaluated in a phase I/II clinical trial. Having previously identified ADCC as potent effector mechanism of MOR202, the capability to induce killing of MM patient cells via antibody dependent cellular phagocytosis (ADCP) was assessed. Furthermore, the immunomodulatory agent lenalidomide (LEN), a commonly used agent in MM therapy was investigated for its potential to enhance the cytotoxicity of MOR202 in vitro and in vivo.
Drug effects in presence or absence of LEN were characterized in vitro in a FACS-based phagocytosis assay using macrophages derived from M-CSF stimulated monocytes and a panel of CD38+ MM target cells. The therapeutic potential of MOR202 in vivo as a single agent and in combination with LEN was studied in a disseminated survival model of iv injected Ramos lymphoma cells. Synergy was determined using the fractional product concept.
MOR202 induced ADCP with high potency showing EC50 values between 40 and 130pM. Maximal killing was donor and cell line dependent ranging from 11 to 72%. The combination with LEN induced additive to synergistic enhancement of MOR202 activity which was mediated by several mechanisms identified to be direct cytotoxicity and increased CD38 expression levels on MM cells. In vivo, MOR202 at 1mg/kg increased median survival (MS) by 142% compared to vehicle control (MS day 48.5 vs. day 20), while LEN had no distinct effect at any of the tested doses between 25 and 100mg/kg (MS day 21–22). Intriguingly, despite the apparent lack of efficacy by LEN alone co-administration of 1mg/kg MOR202 and 100mg/kg LEN resulted in a superior increase of MS by 225% (MS day 65), thus demonstrating strong synergism. Of note, while no mouse survived beyond day 65 in any other group, 3/8 animals in the combo group were completely free of tumor until study termination on day 98.
We here demonstrate ADCP to be an additional potent effector mechanism of MOR202. The combination of MOR202 and LEN enhanced ADCP-mediated killing in vitro and increased median survival in vivo in a synergistic manner. These results suggest a mechanistic rationale for MOR202 combinations with LEN including in particular LEN non-responders or relapse/refractory patients, thus warranting further evaluation in future clinical trials.
Endell:MorphoSys AG: Employment. Boxhammer:MorphoSys AG: Employment. Wurzenberger:MorphoSys AG: Employment. Ness:MorphoSys AG: Employment. Steidl:MorphoSys AG: Employment.
Asterisk with author names denotes non-ASH members.