Background: MOR202, a human anti-CD38 monoclonal antibody, is currently being evaluated in a phase I/IIa clinical trial for the treatment of multiple myeloma (MM). Pharmacodynamically, MOR202 exerts its tumoricidal effect by eliciting antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Aside from a promising single-agent activity profile, experiments in vitro indicate additive or synergistic effects of MOR202 in combination with different types of standard of care compounds in MM such as lenalidomide (LEN) or bortezomib (BOR).
Aims: To compare in vitro the ADCC profile of MOR202 on MM cells and normal hematopoietic cellswith the respective profiles of two other anti-CD38 antibodies in clinical development: daratumumab and isatuximab. To determine the tumoricidal efficacy of MOR202 in vivo in combination with either LEN, BOR or melphalan (MEL), representing immunomodulatory drugs (IMiDs), proteasome inhibitors, and alkylating agents, respectively.
Method: The in vitro ADCC profile of the antibodies was assessed by fluorescence activated cell sorting using a panel of CD38+ MM cell lines in the presence of peripheral blood mononuclear cells. The potential for cytotoxicity towards normal hematopoietic cells was tested on purified natural killer (NK) cells by measuring NK-NK killing. In the in vivo studies, two independent mouse models were employed to assess combinatorial effects. Firstly, as a model for MM, NCI-H929 cells were inoculated intratibially into the bone marrow to establish an orthotopic model characterized by prototypical hallmarks of the disease, such as bone lysis, and the emergence of serum M protein. Bone density, evaluated by microcomputed tomography (μCT), and M protein serum levels were used as endpoint analyses for treatment efficacy. Secondly, as a model for disseminated lymphoma, Ramos non-Hodgkin lymphoma cells were intravenously injected into immunodeficient mice. Survival served as the primary endpoint, reflecting the success of medication. Combinatorial drug interactions were evaluated according to Clarke, 1997 (Breast Cancer Res Treat; 46:255-78) and Chou, 2006 (Pharmacol Rev; 58:621-81).
Results: In the in vitro ADCC studies on MM cell lines, the maximum killing of MOR202 was equivalent to the tested comparator antibodies. In contrast, the potential to induce killing of normal NK cells expressing low levels of CD38 was significantly reduced for MOR202 compared with daratumumab and isatuximab (n=6 donors; median of 7% specific killing vs 30% and 37%, respectively). This appeared to be independent of FcγRIIIa receptor polymorphism status. In the mouse MM model, MOR202 administration at 3 mg/kg significantly reduced bone lysis by up to 72.5%, relative to vehicle control. Treatment with LEN, BOR, or MEL alone also decreased bone lysis significantly, as compared with vehicle control. However, coadministration of MOR202 with LEN, BOR, or MEL completely abolished or dramatically reduced bone lysis (Figure). Drug interaction analyses indicated synergistic efficacy. The markedly reduced bone lysis seen with combination therapy was accompanied by a reduction (>90%) of serum M protein levels indicating a significant decrease in tumor load (Figure). In the disseminated lymphoma model, LEN or BOR administration had no impact on survival time as compared with vehicle control. In contrast, MOR202 treatment resulted in significantly improved survival compared with vehicle control (median 20 and 20.5 days vs 42 and 43.5 days, respectively, in two independent experiments). Notably, coadministration of MOR202/LEN, or MOR202/BOR further improved survival, indicating potentiation of MOR202 activity by agents which by themselves had little effect (i.e., a subtype of synergy). Of note, all mice receiving monotherapy finally succumbed to the tumor. In contrast, 37.5% of mice treated with MOR202/LEN and 40% of mice treated with MOR202/BOR were completely free of tumor until study termination at day 98.
Conclusions: MOR202 shows equivalent ADCC to CD38 high expressing MM cells as compared with daratumumab and isatuximab, while provoking significantly reduced off-tumor killing of CD38 low expressing normal NK cells. In addition, MOR202 acts synergistically in vivo in combination with different compounds representative of classes of agents commonly used in the treatment of hematologic malignancies.
Boxhammer:MorphoSys AG: Employment. Weirather:MorphoSys AG: Employment. Steidl:MorphoSys AG: Employment. Endell:MorphoSys AG: Employment.
Asterisk with author names denotes non-ASH members.