EFFECT OF IMID COMPOUNDS ON CD38 EXPRESSION ON MULTIPLE MYELOMA CELLS: MOR202, A HUMAN CD38 ANTIBODY IN COMBINATION WITH POMALIDOMIDE
Author(s): ,
Rainer Boxhammer
Affiliations:
MorphoSys AG,Martinsried/Planegg,Germany
,
Stefan Steidl
Affiliations:
MorphoSys AG,Martinsried/Planegg,Germany
Jan Endell
Affiliations:
MorphoSys AG,Martinsried/Planegg,Germany
EHA Learning Center. Boxhammer R. Jun 13, 2015; 100777
Disclosure(s): MorphoSys AG
Rainer Boxhammer
Rainer Boxhammer

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Abstract
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Abstract: P636

Type: Poster Presentation

Presentation during EHA20: From 13.06.2015 17:15 to 13.06.2015 18:45

Location: Poster area (Hall C)

Background
MOR202 (MOR03087), a human CD38 antibody currently under evaluation in a phase I/IIa trial, mediates antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP) of multiple myeloma patient-derived cells with high potency (EC50 ~200 pM). 

Aims
To evaluate in vitro the ability of the IMiD compounds lenalidomide and pomalidomide, both of which are approved for multiple myeloma, to modulate CD38 expression and enhance the cytotoxicity of MOR202.

Methods
CD38 expression +/- lenalidomide and +/- pomalidomide on multiple myeloma cell lines was analyzed by flow cytometry. The antitumor activity of pomalidomide combined with MOR202 was evaluated in vitro; analyses included the induction of direct cytotoxicity on multiple myeloma cells and the activation of immune effector cells. On a functional level, the combinatorial effects of MOR202 with pomalidomide were assessed in ADCC assays. Different incubation schemes were used to separate the effect of pomalidomide on target and effector cells, as well as in the evaluation of the combined effects. The observed combination effects were analyzed for synergistic potential using the fractional product concept.

Results
Pomalidomide and lenalidomide mediated a substantial CD38 upregulation on multiple myeloma cell lines. Pomalidomide as a single agent demonstrated activation of effector cells with high potency (EC50 ~150 nM), and demonstrated cytotoxic effects on multiple myeloma cell lines. Additionally, pomalidomide dose-dependently induced an up to 3-fold CD38 upregulation (EC50 ~20 nM) on CD38-expressing multiple myeloma cell lines. Pomalidomide-mediated effects were time-dependent, with the most pronounced effects after 72 h incubation. Combining MOR202 with pomalidomide led to a synergistic enhancement of cytotoxic activity. The synergic benefit ranged 1.2–3.1-fold above theoretical additivity depending on the cell line used, and was most prominent in the case of strong CD38 upregulation.

Summary
Upregulation of CD38 was mediated by both lenalidomide and pomalidomide and may represent a class effect of IMiD compounds. The cytotoxic activity of MOR202 on multiple myeloma cells was enhanced by pomalidomide via multiple mechanisms: direct cytotoxicity, CD38 upregulation and activation of effector cells. These results provide a mechanistic rationale for the combination of MOR202 with IMiD compounds and warrant further clinical evaluation.

Keyword(s): ADCC, Antibody, CD38 expression, Multiple myeloma

Session topic: Multiple myeloma - Biology 2
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