CD38 is expressed in several types of
non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based
therapy.
Daratumumab (
Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R)
multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and
amyloidosis. Here, we have evaluated the activity and mechanism of action of
daratumumab in preclinical in vitro and in vivo models of
mantle cell lymphoma (MCL),
follicular lymphoma (FL) and
diffuse large B-cell lymphoma (DLBCL), as monotherapy or in combination with standard chemo-
immunotherapy. In vitro,
daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all
lymphoma subtypes. In the presence of human serum,
complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that
daratumumab fully penetrated a three-dimensional (3D)
lymphoma organoid and decreased organoid volume. In vivo,
daratumumab completely prevents
tumor outgrowth in models of MCL and FL, and shows comparable activity to
rituximab in a disseminated in vivo model of blastic MCL. Moreover,
daratumumab improves overall survival (OS) in a mouse model of transformed CD20dim FL, where
rituximab showed limited activity.
Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in MCL and FL xenografts. Furthermore, in a patient-derived DLBCL xenograft model,
daratumumab anti-
tumor activity was comparable to R-CHOP and the addition of
daratumumab to either CHOP or R-CHOP led to full
tumor regression. In summary,
daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development.