Bone Marrow Research Multiple Myeloma Multiple Myeloma Bone Marrow Research Multiple Myeloma Copyright © 2011 Hindawi Publishing Corporation. All rights reserved. This is a focus issue published in volume 2011 of “Bone Marrow Research.” All articles are open access articles distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board Joseph H. Antin, USA Hans Jochem Kolb, Germany PeterJ.Quesenberry,USA Igor W. Blau, Germany Robert B. Levy, USA Shahin Rafii, USA Catherine Bollard, USA Mark R. Litzow, USA Voravit Ratanatharathorn, USA Paolo De Fabritiis, Italy Fausto Loberiza, USA David A. Rizzieri, USA Yigal Dror, Canada David Ma, Australia Patrick J. Stiff,USA Csar O. Freytes, USA Ignazio Majolino, Italy Anna Sureda, Spain A. Ganser, Germany Philip L. McCarthy, USA Guido J. K. Tricot, USA Eva C. Guinan, USA Kenneth R. Meehan, USA Celalettin Ustun, USA Kais Hussein, Germany Paul V. O’Donnell, USA Catherine Verfaillie, Belgium Issa F. Khouri, USA Helen A. Papadaki, Greece Axel R. Zander, Germany Hans Klingemann, USA Finn B. Petersen, USA Guido Kobbe, Germany Luis F. Porrata, USA Contents Antibody-Based Therapies in Multiple Myeloma, Yu-Tzu Tai and Kenneth C. Anderson Volume 2011, Article ID 924058, 14 pages A Case of Monoclonal Lymphoplasmacytosis of the Bone Marrow with IgM-Positive Russell Bodies, Hidekazu Kayano, Tsuneyuki Shimada, Naoki Wakimoto, Yuichi Nakamura, Masami Bessho, Hiroshi Yamaguchi, Atsushi Sasaki, and Michio Shimizu Volume 2011, Article ID 814372, 3 pages Immune Recovery after Cyclophosphamide Treatment in Multiple Myeloma: Implication for Maintenance Immunotherapy, Amir Sharabi and Nechama Haran-Ghera Volume 2011, Article ID 269519, 7 pages Recent Advances in the Pathogenesis and Management of Cast Nephropathy (Myeloma Kidney), Stephanie Stringer, Kolitha Basnayake, Colin Hutchison, and Paul Cockwell Volume 2011, Article ID 493697, 9 pages Oncolytic Virotherapy for Multiple Myeloma: Past, Present, and Future, Chandini M. Thirukkumaran and Don G. Morris Volume 2011, Article ID 632948, 10 pages Multiple Myeloma: A Review of Imaging Features and Radiological Techniques,C.F.Healy,J.G.Murray, S. J. Eustace, J. Madewell, P. J. O’Gorman, and P. O’Sullivan Volume 2011, Article ID 583439, 9 pages Hindawi Publishing Corporation Bone Marrow Research Volume 2011, Article ID 924058, 14 pages doi:10.1155/2011/924058 Review Article Antibody-Based Therapies in Multiple Myeloma Yu-Tzu Tai and Kenneth C. Anderson Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA Correspondence should be addressed to Yu-Tzu Tai, yu-tzu [email protected] Received 18 October 2010; Accepted 4 January 2011 Academic Editor: Ignazio Majolino Copyright © 2011 Y.-T. Tai and K. C. Anderson. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The unmet need for improved multiple myeloma (MM) therapy has stimulated clinical development of monoclonal antibodies (mAbs) targeting either MM cells or cells of the bone marrow (BM) microenvironment. In contrast to small-molecule inhibitors, therapeutic mAbs present the potential to specifically target tumor cells and directly induce an immune response to lyse tumor cells. Unique immune-effector mechanisms are only triggered by therapeutic mAbs but not by small molecule targeting agents. Although therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, the advancement of genetic recombination for humanizing rodent mAbs has allowed large-scale production and designation of mAbs with better affinities, efficient selection, decreasing immunogenicity, and improved effector functions. These advancements of antibody engineering technologies have largely overcome the critical obstacle of antibody immunogenicity and enabled the development and subsequent Food and Drug Administration (FDA) approval of therapeutic Abs for cancer and other diseases. 1. Introduction interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), Receptor Activator of NFκB ligand (RANKL) (also Despite the landmark approval of the anti-CD20 mAb rit- known as osteoprotegerin ligand (OPGL)), and Dickkopf uximab for the treatment of B-cell malignancies, to date, no homolog 1 (DKK1) are among those under clinical evalu- mAb-based therapy has been approved for MM treatment. ation. Specifically, targeting bone-MM cell interactions via ff The development of e ective cytotoxic mAb therapies in MM bone biology modulating factors such as DKK1 and RANKL has been hindered by the lack of uniquely and constitutively is likely to trigger anti-MM effects but also improves bone expressed target molecules on all MM cells. Indeed, studies in disease thereby improving both patient survival as well as early 2000 demonstrated only minimal activity of anti-CD20 patient’s quality of life. rituximab and antibodies against plasma cell-specific CD38 In the coming years, the preclinical progress in defining ff antibodies in MM [1–4]. However, numerous e orts to iden- novel MM markers will be continued and subsequently will tify new targets on MM cells including gene expression pro- advance the clinical development of therapeutic mAbs, alone filing and oncogenomic studies are under way. Derived mAbs or in combination with other anti-MM agents, to improve (e.g., against CD40, HM1.24, IGF-1R, CD56, CS1, CD138, patient outcome in MM. CD74, IL-6R, CD38, TRAIL-R1, and the activin receptor type IIA (ActRIIA)) have already demonstrated promising preclinical as well as early clinical activity (Table 1). 2. Mechanisms of Action of Therapeutic Given the importance of the bone marrow (BM) mi- Monoclonal Antibodies croenvironment for MM cell growth, survival, and drug resistance, mAbs have been additionally designed to func- Antibodies of IgG, the most commonly used immunoglob- tionally block both autocrine and paracrine secreted ulin form in cancer therapy, are unique proteins with dual cytokines and growth factors as well as molecules mediating functionality. Therapeutic mAbs use one or more following MM-stromal cell interaction. For example, mAbs targeting mechanisms (Figure 1) to reduce tumor burden in patients. 2 Table 1: Antigens targeted by antibodies in multiple myeloma in different stages of preclinical/clinical development. Type of mAb Target Brand name Company/Sponsor Phase Remarks (conjugate) the maytansinoid CD138 B-B4-DM1 ImmunoGen immunoconjugate preclinical Tassone Blood 2004,104:3688–96 mouse IgG1 mAb B-B4 Chugai HM1.24 humanized HM1.24 humanized preclincial Ozaki Blood 1999,93:3922–3930 Pharmaceutical Fc-engineered humanized HM1.24 Xencor Inc preclincial humanized IgG1 OPi EUSA Pharma; OP-R003-1, 1339 IL-6 Vaccinex licensed to human IgG1 preclincial Fulciniti Clin Cancer Res 2009,15:7144–52 Elsilimomab, Azintrel Glaxo Smith Kline HLA-DR 1D09C3 GPC Biotech, AG human IgG1 preclincial Carlo-Stella Cancer Res 2007 Sainz Cancer Immunol Immunother 2006 C11C1 mAb inhibits its own tumor growth in vivo, slows down B38-MM growth rate when both MM Temple Universit y are implanted together and when mAb C11C1 is injected kininogen C11C1 mouse preclincial School of Medicine intraperitoneally. MAb C11C1-treated-MM showed decreased MVD and kininogen binding in vivo without FGF-2, B1R, or B2R expression changes Chugai converted from mouse Sekimoto Cancer Res 2007; 67:1184–92. a recombinant single-chain Fv HLA class I 2D7-DB Pharmaceutical Co. IgG2b, single-chain Fv preclincial diabody 2D7-DB specifically induces multiple myeloma cell death in the Ltd. diabody bone marrow environment Yang Blood 2007; 110:3028–35. & Clin Cancer Res 2009; 15:951–9. β2- MD Anderson anti-β2M mAbs mouse preclincial Strong apoptotic effect on myeloma cells and low toxocity in the mice microglobulin Cancer Center suppports potential use as therapeutic agents CD38 MOR202 MorphoSys AG human IgG1 preclincial Tesar et al. J. Clin Oncol 2007, 25(18S): 8106 Zhou Blood 2008; 111:549–557. humanized 2B6 MoAb may target in patients with systemic AL-amyloidosis. It blocks Fc engagement of CD32B MGA321(2B6) MacroGenics humanized IgG1 preclincial CD32B and may improve the performance of other cancer Mabs when combined with them during administration Trudel Blood 2006; 2:4908–4915. The inhibitory anti-FGFR3 antibody, FGFR3 PRO-001 Prochon Biotech Ltd. human IgG1 preclincial PRO-001, is cytotoxic to t(4;14) MM cells and deserves further study for Bone Marrow Research the treatment of FGFR3-expressing myeloma Smallshaw J Immunother 2004; Coleman J Immunother 2006 cUV3 ICAM-1 cUV3 Abiogen chimeric IgG1 preclincial significantly prolongs the survival of SCID/ARH-77 mice Fusion protein of an BLyS BLyS/rGel Targa Therapeutics antibody tethered to a preclincial Lyu et al. Mol Cancer Ther 2007; 6:460–70 toxin TACI Atacicept (TACI-Ig) ZymoGenetics Inc. fusion protein preclincial Yaccoby Leukemia 2008 22, 406–413 Bone Marrow Research Table 1: Continued. Type of mAb Target Brand name Company/Sponsor Phase Remarks (conjugate) CD70 SGN-70 Seatle Genetics humanized IgG1 preclincial McEarchern Clin Cancer Res 2008 14, 7763–72 TRAIL- Human Genome lexatumumab human preclincial Menoret et al. Blood 2006;132: 1356–62 R2(DR5) Sciences a single-chain fragment format Yoshio-Hoshino Cancer Res 2007; 67:871–5. the NRI gene introduction