Abstract
SGN-40, a humanized immoglobulin G1 (IgG1) anti-CD40 monoclonal antibody, mediates cytotoxicity against human multiple myeloma (MM) cells via suppression of interleukin (IL)-6-induced proliferative and antiapoptotic effects as well as antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we studied the clinical significance of an immunomodulatory drug lenalidomide on SGN-40-induced cytotoxicity against CD138(+)CD40(+) MM lines and patient MM cells. Pretreatment with lenalidomide sensitized MM cells to SGN-40-induced cell death. Combined lenalidomide and SGN-40 significantly induced MM apoptosis, evidenced by enhanced cleavage of caspase-3/8/poly(ADP-ribose)polymerase and increased sub-G(0) cells, compared with either single agent at the same doses. Pretreatment of effector cells with lenalidomide augmented SGN-40-induced MM cell lysis, associated with an increased number of CD56(+)CD3(-) natural killer (NK) cells expressing CD16 and LFA-1. Importantly, pretreatment with lenalidomide or lenalidomide and SGN-40 markedly enhanced NK-cell-mediated lysis of autologous patient MM cells triggered by SGN-40. Lenalidomide also up-regulated CD40L on CD56(+)CD3(-) NK cells, facilitating IL-2-mediated activation of NK cells. In addition, lenalidomide induced the CD56(dim) NK subset, which are more potent mediators of ADCC against target MM cells than the CD56(bright) NK subset. Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40-mediated ADCC against CD40-expressing MM cells. These studies, therefore, show that the addition of lenalidomide to SGN-40 enhances cytotoxicity against MM cells, providing the framework for combined lenalidomide and SGN-40 in a new treatment paradigm to both target MM cells directly and induce immune effectors against MM.
Highlights
Clinical efficacy of monoclonal antibody and mAb-based therapies has been shown in both hematologic and solid tumors; for example, anti-CD20 rituximab, the first Food and DrugI2005 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-05-1657Administration–approved mAb for the treatment of cancer, is broadly used to treat non-Hodgkin’s lymphoma and other B-cell lymphoproliferative diseases
We found that double-positive natural killer (NK) cells (CD16+CD56+CD3À as well as LFA-1+CD56+CD3À) were increased f2-fold by lenalidomide or the combination of SGN-40 and lenalidomide relative to complete medium alone, SGN-40, or control immoglobulin G1 (IgG1) (Fig. 4D)
We showed that pretreatment of effector cells with lenalidomide increased SGN-40–mediated antibody-dependent cell-mediated cytotoxicity (ADCC) against MM cells, associated with an increased number of CD56+CD3À NK cells expressing both CD16 and LFA-1
Summary
Administration–approved mAb for the treatment of cancer, is broadly used to treat non-Hodgkin’s lymphoma and other B-cell lymphoproliferative diseases. This type of passive immunotherapy can be effective even if the host immune system is compromised. SGN-40 is composed of the human IgG1 class constant region, as in anti-CD20 rituximab, coupled with humanized murine variable regions against CD40 [4, 5] It binds to CD40 on MM cells and triggers antibody-dependent cell-mediated cytotoxicity (ADCC) against CD40-expressing MM cell lines and patient cells [5], as well as down-regulates interleukin (IL)-6 receptor on MM cells, thereby inhibiting IL-6-mediated survival and growth signals [4]. These preclinical data support a potential therapeutic use of SGN-40 to improve patient outcome of MM
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