Leukemia (2012) 26, 199–213 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu REVIEW Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma NWCJ van de Donk1, S Kamps1, T Mutis2 and HM Lokhorst1 1Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands and 2Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands The introduction of autologous stem cell transplantation the myeloma patients achieved a partial response (PR) or stable combined with the introduction of immunomodulatory drugs disease following rituximab therapy. All these patients expressed (IMiDs) and proteasome inhibitors has significantly improved CD20 on their myeloma cells.2 However, as only B15–20% of survival of multiple myeloma patients. However, ultimately the majority of patients will develop refractory disease, indicating all myeloma patients express CD20 on their bone marrow the need for new treatment modalities. In preclinical and clinical plasma cells, new targets for immunotherapy need to be studies, promising results have been obtained with several identified. The search for other targets has led to the develop- monoclonal antibodies (mAbs) targeting the myeloma tumor ment of mAbs targeting growth factor receptors or adhesion cell or the bone marrow microenvironment. The mechanisms molecules on myeloma cells. Other newly developed mAbs underlying the therapeutic efficacy of these mAbs include are directed against cellular or non-cellular components of the direct induction of tumor cell apoptosis via inhibition or activation of target molecules, complement-dependent cyto- bone marrow microenvironment, resulting in the neutraliza- toxicity and antibody-dependent cell-mediated cytotoxicity tion of growth factors, inhibition of angiogenesis, modulation (ADCC). The capability of IMiDs to enhance ADCC and the of mediators of bone disease and enhancement of the host modulation of various important signaling cascades in myelo- antitumor immune response (Figure 1 and Table 1). ma cells by both bortezomib and IMiDs forms the rationale to Besides direct effects via modulation of the activity of the combine these novel agents with mAbs as new treatment targeted antigen, mAbs can also induce tumor cell death strategies for myeloma patients. In this review, we will give an overview of various mAbs directly targeting myeloma tumor via complement-dependent cytotoxicity (CDC) and antibody- cells or indirectly via effects on the bone marrow micro- dependent cell-mediated cytotoxicity (ADCC) (Figure 2). The environment. Special focus will be on the combination of these process of ADCC is achieved through activation of Fc receptors mAbs with IMiDs or bortezomib. on myeloid and natural killer (NK) effector cells by tumor cell- Leukemia (2012) 26, 199–213; doi:10.1038/leu.2011.214; attached immunoglobins. Subsequent cytotoxicity is mediated published online 19 August 2011 through at least two different mechanisms: one involving the Keywords: multiple myeloma; immunotherapy; monoclonal antibody; immunomodulatory drugs; proteasome inhibitor; bone release of perforin and granzymes from effector cells, and the marrow micro-environment other involving death ligands Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). CDC is depen- dent on the interaction of the antibody Fc domains with the classic complement-activating protein C1q. There is also Introduction evidence that uptake of antibody-opsonized tumor cells and cellular fragments by antigen-presenting cells is associated with The introduction of autologous stem cell transplantation and enhanced antigen presentation, leading to tumor-specific T-cell 3 novel agents such as the proteasome inhibitor bortezomib and responses. the immunomodulatory drugs (IMiDs) thalidomide and lenali- The capability of IMiDs to activate multiple arms of the 4,5 domide has significantly improved survival of myeloma patient’s immune system including enhanced ADCC com- patients.1 However, the majority of myeloma patients ultimately bined with the modulation of various important signaling develop refractory disease, underscoring the need for new cascades in myeloma cells by both bortezomib and IMiDs therapeutic approaches. The search for new strategies has led forms the rationale to combine these novel agents with mAbs as not only to the development of second-generation immuno- new treatment strategies for myeloma patients. In this review, modulatory drugs (IMiDs) and proteasome inhibitors, but also we will give an overview of various classes of mAbs at different to compounds with different mechanisms of action, such stages of clinical development (Table 1). mAbs with similar as histone deacetylase inhibitors, Akt inhibitors and mTOR mechanisms of action are grouped together. Special focus will inhibitors. In addition, the successful application of immuno- be on mAbs that are currently being evaluated in clinical trials therapeutics such as the anti-CD20 monoclonal antibody and on combinations of these mAbs with IMiDs (Table 2) or (mAb) rituximab, the anti-CD52 mAb alemtuzumab and, most bortezomib (Table 3). recently, the anti-CD30–drug conjugate brentuximab vedotin in non-Hodgkin’s lymphoma, Hodgkin’s lymphoma and chronic lymphocytic leukemia has stimulated the development of mAbs targeting proteins involved in myeloma cell adhesion mAbs applicable for myeloma treatment. Interestingly, 32% of Myeloma cells interact with various cellular and non-cellular Correspondence: Dr NWCJ van de Donk, Department of Hematology, components of the bone marrow microenvironment, which University Medical Center Utrecht, Heidelberglaan 100, Utrecht promotes tumor growth, protects against antimyeloma agents, 3584CX, The Netherlands. E-mail: [email protected] leads to bone destruction and increases susceptibility to 6 Received 27 May 2011; accepted 5 July 2011; published online 19 infections by impairing the immune system. Adhesion is August 2011 mediated by cellular receptors and results in the activation of Monoclonal antibody-based therapy in myeloma NWCJ van de Donk et al 200 mAbs targeting mediators of NF-κB bone disease RANKL↑, OPG↓ mAbs targeting α β β Notch-1 growth factors TNF- , TGF- , IL-1 , IL-6, IGF-I, Stromal cell and receptors bFGF, IL-6, VEGF VEGF, WNT Raf NF-κB mAbs inhibting PI-3K JAK Adhesion MEK β-catenin Notch-1 adhesion molecules molecules Akt STAT3 P42/44 MAPK Anti-apoptosis Drug resistance Proliferation Growth factors VEGF, FGF-2, TNF-α, Proliferation Anti-apoptosis α Osteoclast TGF-, MMPs Drug resistance RANKL, MIP-1 Endothelial Myeloma cell cell VEGF, FGF-2, MMPs Fibronectine mAbs targeting VEGF, IL-6, VEGF, IL-6, mAbs targeting growth factors TGF-β, IL-10 TGF-β, IL-10 mediators of and recetors bone disease mAbs PD-1/PD-L1, KIR targeting VEGF, IL-6, growth factors DKK1, Bone resorption ↑ TGF-β, IL-10 mAbs and receptors activating sFRP-2 Bone formation ↓ NK cells Angiogenesis PD-1/PD-L1, CD200/CD200R mAbs B cell activating T cells T cell NK cell Immune deficiency Osteoblast Dendritic cell Figure 1 Targets of mAbs in multiple myeloma. Several mAbs that are currently being evaluated in clinical trials target important growth factor receptors and adhesion molecules present on myeloma cells. This will result in the inhibition of important signaling cascades and impair adhesion of myeloma cells to other cells in the bone marrow microenvironment. Other mAbs are directed against important cellular and non-cellular components of the microenvironment including growth factors, mediators of bone disease, T cells and NK cells. This results in neutralization of growth factors such as IL-6 or IGF-1, blockage of angiogenesis, inhibition of bone resorption, improvement of bone formation and enhancement of the host antitumor immune response. important signaling cascades in both the myeloma cell and against myeloma cells.7,9 Furthermore, the combination of stromal cell, leading to protection against apoptosis and elotuzumab plus bortezomib resulted in improved antitumor increased production of several myeloma growth factors, activity in a mouse model.9 including interleukin-6 (IL-6), insulin growth factor-1 (IGF-1) Preliminary results from ongoing trials show encouraging and vascular endothelial growth factor (VEGF). Over the past results with acceptable toxicity for elotuzumab combination few years, various mAbs targeting adhesion molecules present therapy. No dose-limiting toxicity (DLT) was reported in a phase on myeloma cells showed great promise in both preclinical and 1 study evaluating elotuzumab 5, 10 or 20 mg on days 1, 8, 15 early clinical studies. and 22 of a 28-day cycle in combination with lenalidomide and dexamethasone. In this study of mostly lenalidomide-naı¨ve patients, at least PR was achieved in 82% of patients.10 In a CS1 phase 2 trial in lenalidomide-naı¨ve myeloma patients with a CS1 is a cell surface glycoprotein involved in myeloma cell median of two previous therapies, the combination of elotuzu- adhesion to bone marrow stromal cells.7,8 High expression of mab and lenalidomide plus dexamethasone was feasible with CS1 has been observed in multiple myeloma cell lines and in 85% at least PR.11 Two ongoing phase 3 trials will provide the majority of myeloma cells from patients (CS1 mRNA additional data to define the value of addition of elotuzumab to expressed by more than 97% of myeloma cells), whereas CS1 lenalidomide/dexamethasone in relapsed/refractory