Synergistic in Vitro Activity of MOR202, a Human CD38 Antibody, in Combination with Pomalidomide

Background: MOR202 is a fully human anti-CD38 antibody currently being tested in a Phase I/IIa clinical trial in multiple myeloma (MM). It mediates antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in MM cells with high potency (EC50 ~200 pM) representing a possible promising new therapy for MM patients. In this in vitro study, we evaluated the synergistic potential of MOR202 and pomalidomide (POM), a newly approved IMiD^® immunomodulatory agent in MM therapy.

Methods: Using flow cytometry analysis, POM was evaluated in relation to its effects on several parameters anticipated to be relevant for anti-tumor activity when combined with MOR202. This included the induction of direct cytotoxicity and CD38 upregulation in several MM cell lines, as well as the activation of human immune effector cells derived from peripheral blood mononuclear cells of healthy donors. On a functional level the interaction of MOR202 and POM was assessed using FACS-based ADCC assays. Different incubation schemes prior to the ADCC assays were evaluated in order to distinguish the influence of POM on ADCC activity when pre-incubated for 72 hours either on target or effector cells or on both in parallel. The observed combination effects were analyzed for synergistic potential. Experiments were carried out in triplicate and mean values (±SEM) were calculated.

Results: POM as a single agent showed cytotoxic effects on MM cell lines with high potency (EC50 ~150 nM) and additionally induced an up to 2.7-fold upregulation of CD38 (EC50 ~20 nM) on CD38-expressing MM cell lines. Both effects were maximal at the last tested time point of 72 hours and strongest on cell lines with comparably lower CD38 expression levels. In combination with the observed activation of effector cells these POM-mediated mechanisms lead to a synergistically enhanced cytotoxic activity of MOR202. This synergistic benefit ranged between 1.2-fold and 3.1-fold above theoretical additivity depending on the cell line used and was most pronounced in the case of strong CD38 upregulation.

Figure 1

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Exemplary ADCC dose-response curves for the comparably lower CD38 expressing cell line AMO-1 after POM pre-treatment of effector cells, target cells or both.

Figure 1

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Exemplary ADCC dose-response curves for the comparably lower CD38 expressing cell line AMO-1 after POM pre-treatment of effector cells, target cells or both.

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Conclusions: The cytotoxic activity of MOR202 on MM cells was enhanced and synergized when combined with the immunomodulator agent POM via multiple mechanisms, namely direct cytotoxicity, CD38 upregulation and activation of effector cells. These results provide a mechanistic rationale for combining MOR202 and POM and warrant further evaluation in the clinical setting.