A recombinant triplebody with specificity for CD19 and HLA-DR mediates 
preferential binding to antigen double-positive cells by dual-targeting

References

• Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nat Biotechnol 2005; 23:1147 - 1157; PMID: 16151408; http://dx.doi.org/10.1038/nbt1137
   PubMed Web of Science ®Google Scholar
• Duebel S. Handbook of Therapeutic Antibodies 2007 Weinheim WILEY-VCH
   Google Scholar
• Weiner LM, Dhodapkar MV, Ferrone S. Monoclonal antibodies for cancer immunotherapy. Lancet 2009; 373:1033 - 1040; PMID: 19304016; http://dx.doi.org/10.1016/S0140-6736(09)60251-8
   PubMed Web of Science ®Google Scholar
• Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008; 321:974 - 977; PMID: 18703743; http://dx.doi.org/10.1126/science.1158545
   PubMed Web of Science ®Google Scholar
• Clynes R. Antitumor antibodies in the treatment of cancer: Fc receptors link opsonic antibody with cellular immunity. Hematol Oncol Clin North Am 2006; 20:585 - 612; PMID: 16762726; http://dx.doi.org/10.1016/j.hoc.2006.02.010
   PubMed Web of Science ®Google Scholar
• de Haij S, Jansen JH, Boross P, Beurskens FJ, Bakema JE, Bos DL, et al. In vivo cytotoxicity of type I CD20 antibodies critically depends on Fc receptor ITAM signaling. Cancer Res 2010; 70:3209 - 3217; PMID: 20354182; http://dx.doi.org/10.1158/0008-5472.CAN-09-4109
   PubMed Web of Science ®Google Scholar
• Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, Ivanchenko VV, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int J Cancer 2010; 127:2209 - 2221
   PubMed Web of Science ®Google Scholar
• Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 2008; 26:1789 - 1796; PMID: 18347005; http://dx.doi.org/10.1200/JCO.2007.14.8957
   PubMed Web of Science ®Google Scholar
• Topp MGN, Kufer P, Zugmaier G, Degenhard E, Neumann S, Horst HA, et al. Treatment with anti-CD19 BiTE antibody blinatumomab (MT103/MEDI-538) is able to eliminate minimal residual disease (MRD) in patients with B-precursor acute lmphoblastic leukemia (ALL): first results of an ongoing phase II study (ASH Annual Meeting Abstract). Blood 2008; 112:1926
   Google Scholar
• Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M, et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007; 25:3712 - 3718; PMID: 17704420; http://dx.doi.org/10.1200/JCO.2006.08.8021
   PubMed Web of Science ®Google Scholar
• Topp MS, Kufer P, Gokbuget N, Goebeler M, Klinger M, Neumann S, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 2011; 29:2493 - 2498; PMID: 21576633; http://dx.doi.org/10.1200/JCO.2010.32.7270
   PubMed Web of Science ®Google Scholar
• Bluemel C, Hausmann S, Fluhr P, Sriskandarajah M, Stallcup WB, Baeuerle PA, et al. Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen. Cancer Immunol Immunother 2010; 59:1197 - 1209; PMID: 20309546; http://dx.doi.org/10.1007/s00262-010-0844-y
   PubMed Web of Science ®Google Scholar
• Kellner C, Bruenke J, Stieglmaier J, Schwemmlein M, Schwenkert M, Singer H, et al. A novel CD19-directed recombinant bispecific antibody derivative with enhanced immune effector functions for human leukemic cells. J Immunother 2008; 31:871 - 884; PMID: 18833000; http://dx.doi.org/10.1097/CJI.0b013e318186c8b4
   PubMed Web of Science ®Google Scholar
• Kügler M, Stein C, Kellner C, Mentz K, Saul D, Schwenkert M, et al. A recombinant trispecific single-chain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting. Br J Haematol 2010; 150:574 - 586; PMID: 10.1111/j.1365-2141.2010.08300.x
   PubMed Web of Science ®Google Scholar
• Schubert I, Kellner C, Stein C, Kugler M, Schwenkert M, Saul D, et al. A single-chain triplebody with specificity for CD19 and CD33 mediates effective lysis of mixed lineage leukemia cells by dual targeting. MAbs 2011; 3:21 - 30; PMID: 21081841; http://dx.doi.org/10.4161/mabs.3.1.14057
   PubMed Web of Science ®Google Scholar
• Singer H, Kellner C, Lanig H, Aigner M, Stockmeyer B, Oduncu F, et al. Effective elimination of acute myeloid leukemic cells by recombinant bispecific antibody derivatives directed against CD33 and CD16. J Immunother 2010; 33:599 - 608; PMID: 20551837; http://dx.doi.org/10.1097/CJI.0b013e3181dda225
   PubMed Web of Science ®Google Scholar
• Bruenke J, Barbin K, Kunert S, Lang P, Pfeiffer M, Stieglmaier K, et al. Effective lysis of lymphoma cells with a stabilised bispecific single-chain Fv antibody against CD19 and FcgammaRIII (CD16). Br J Haematol 2005; 130:218 - 228; PMID: 16029450; http://dx.doi.org/10.1111/j.1365-2141.2005.05414.x
   PubMed Web of Science ®Google Scholar
• Kügler M, Stein C, Schwenkert M, Saul D, Vockentanz L, Huber T, et al. Stabilization and humanization of a single-chain Fv antibody fragment specific for human lymphocyte antigen CD19 by designed point mutations and CDR-grafting onto a human framework. Protein Eng Des Sel 2009; 22:135 - 147; PMID: 19188138; http://dx.doi.org/10.1093/protein/gzn079
   PubMed Web of Science ®Google Scholar
• Baum W, Steininger H, Bair HJ, Becker W, Hansen-Hagge TE, Kressel M, et al. Therapy with CD7 monoclonal antibody TH-69 is highly effective for xenografted human T-cell ALL. Br J Haematol 1996; 95:327 - 338; PMID: 8904888; http://dx.doi.org/10.1046/j.1365-2141.1996.d01-1900.x
   PubMed Web of Science ®Google Scholar
• Beckhove P, Warta R, Lemke B, Stoycheva D, Momburg F, Schnolzer M, et al. Rapid T cell-based identification of human tumor tissue antigens by automated two-dimensional protein fractionation. J Clin Invest 2010; 120:2230 - 2242; PMID: 20458140; http://dx.doi.org/10.1172/JCI37646
   PubMed Web of Science ®Google Scholar
• Preuss KD, Zwick C, Bormann C, Neumann F, Pfreundschuh M. Analysis of the B-cell repertoire against antigens expressed by human neoplasms. Immunol Rev 2002; 188:43 - 50; PMID: 12445280; http://dx.doi.org/10.1034/j.1600-065X.2002.18805.x
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004; 10:909 - 915; PMID: 15340416; http://dx.doi.org/10.1038/nm1100
   PubMed Web of Science ®Google Scholar
• Burkhardt C, Himmelein S, Britt W, Winkler T, Mach M. Glycoprotein N subtypes of human cyto-megalovirus induce a strain-specific antibody response during natural infection. J Gen Virol 2009; 90:1951 - 1961; PMID: 19420160; http://dx.doi.org/10.1099/vir.0.010967-0
   PubMed Web of Science ®Google Scholar
• Baldick CJ Jr, Shenk T. Proteins associated with purified human cytomegalovirus particles. J Virol 1996; 70:6097 - 6105; PMID: 8709233
   PubMed Web of Science ®Google Scholar
• Mantovani B, Rabinovitch M, Nussenzweig V. Phagocytosis of immune complexes by macrophages. Different roles of the macrophage receptor sites for complement (C3) and for immunoglobulin (IgG). J Exp Med 1972; 135:780 - 792; PMID: 5018051; http://dx.doi.org/10.1084/jem.135.4.780
   PubMed Web of Science ®Google Scholar
• Olejniczak SH, Stewart CC, Donohue K, Czuczman MS. A quantitative exploration of surface antigen expression in common B-cell malignancies using flow cytometry. Immunol Invest 2006; 35:93 - 114; PMID: 16531332; http://dx.doi.org/10.1080/08820130500496878
   PubMed Web of Science ®Google Scholar
• Lillemeier BF, Pfeiffer JR, Surviladze Z, Wilson BS, Davis MM. Plasma membrane-associated proteins are clustered into islands attached to the cytoskeleton. Proc Natl Acad Sci USA 2006; 103:18992 - 18997; PMID: 17146050; http://dx.doi.org/10.1073/pnas.0609009103
   PubMed Web of Science ®Google Scholar
• Vallera DA, Todhunter DA, Kuroki DW, Shu Y, Sicheneder A, Chen H. A bispecific recombinant immunotoxin, DT2219, targeting human CD19 and CD22 receptors in a mouse xenograft model of B-cell leukemia/lymphoma. Clin Cancer Res 2005; 11:3879 - 3888; PMID: 15897589; http://dx.doi.org/10.1158/1078-0432.CCR-04-2290
   PubMed Web of Science ®Google Scholar
• Robinson MK, Hodge KM, Horak E, Sundberg AL, Russeva M, Shaller CC, et al. Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro. Br J Cancer 2008; 99:1415 - 1425; PMID: 18841159; http://dx.doi.org/10.1038/sj.bjc.6604700
   PubMed Web of Science ®Google Scholar
• Dick JE. Stem cell concepts renew cancer research. Blood 2008; 112:4793 - 4807; PMID: 19064739; http://dx.doi.org/10.1182/blood-2008-08-077941
   PubMed Web of Science ®Google Scholar
• Hosen N, Park CY, Tatsumi N, Oji Y, Sugiyama H, Gramatzki M, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci USA 2007; 104:11008 - 11013; PMID: 17576927; http://dx.doi.org/10.1073/pnas.0704271104
   PubMed Web of Science ®Google Scholar
• Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 2009; 138:271 - 285; PMID: 19632178; http://dx.doi.org/10.1016/j.cell.2009.05.046
   PubMed Web of Science ®Google Scholar
• Jin L, Lee EM, Ramshaw HS, Busfield SJ, Peoppl AG, Wilkinson L, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 2009; 5:31 - 42; PMID: 19570512; http://dx.doi.org/10.1016/j.stem.2009.04.018
   PubMed Web of Science ®Google Scholar
• Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 2000; 14:1777 - 1784; PMID: 11021753; http://dx.doi.org/10.1038/sj.leu.2401903
   PubMed Web of Science ®Google Scholar
• van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood 2007; 110:2659 - 2666; PMID: 17609428; http://dx.doi.org/10.1182/blood-2007-03-083048
   PubMed Web of Science ®Google Scholar
• Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G, et al. Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 2005; 106:4086 - 4092; PMID: 16131573; http://dx.doi.org/10.1182/blood-2005-03-1072
   PubMed Web of Science ®Google Scholar
• Meeker TC, Miller RA, Link MP, Bindl J, Warnke R, Levy R. A unique human B lymphocyte antigen defined by a monoclonal antibody. Hybridoma 1984; 3:305 - 320; PMID: 6441771; http://dx.doi.org/10.1089/hyb.1984.3.305
   PubMed Web of Science ®Google Scholar
• Fleit HB, Wright SD, Unkeless JC. Human neutrophil Fc gamma receptor distribution and structure. Proc Natl Acad Sci USA 1982; 79:3275 - 3279; PMID: 6808506; http://dx.doi.org/10.1073/pnas.79.10.3275
   PubMed Web of Science ®Google Scholar
• Greil J, Gramatzki M, Burger R, Marschalek R, Peltner M, Trautmann U, et al. The acute lymphoblastic leukaemia cell line SEM with t(4;11) chromosomal rearrangement is biphenotypic and responsive to interleukin-7. Br J Haematol 1994; 86:275 - 283; PMID: 8199015; http://dx.doi.org/10.1111/j.1365-2141.1994.tb04726.x
   PubMed Web of Science ®Google Scholar
• Sambrook J, Russel DW. Molecular Cloning: A Laboratory Manual 2001; NY Cold Spring Harbour
   Google Scholar
• Lang P, Barbin K, Feuchtinger T, Greil J, Peipp M, Zunino SJ, et al. Chimeric CD19 antibody mediates cytotoxic activity against leukemic blasts with effector cells from pediatric patients who received T-cell-depleted allografts. Blood 2004; 103:3982 - 3985; PMID: 14764538; http://dx.doi.org/10.1182/blood-2003-05-1735
   PubMed Web of Science ®Google Scholar
• Peipp M, Kupers H, Saul D, Schlierf B, Greil J, Zunino SJ, et al. A recombinant CD7-specific single-chain immunotoxin is a potent inducer of apoptosis in acute leukemic T cells. Cancer Res 2002; 62:2848 - 2855; PMID: 12019163
   PubMed Web of Science ®Google Scholar
• Stein C, Kellner C, Kugler M, Reiff N, Mentz K, Schwenkert M, et al. Novel conjugates of single-chain Fv antibody fragments specific for stem cell antigen CD123 mediate potent death of acute myeloid leukaemia cells. Br J Haematol 2010; 148:879 - 889; PMID: 20064159; http://dx.doi.org/10.1111/j.1365-2141.2009.08033.x
   PubMed Web of Science ®Google Scholar
• Bruenke J, Fischer B, Barbin K, Schreiter K, Wachter Y, Mahr K, et al. A recombinant bispecific single-chain Fv antibody against HLA class II and FcgammaRIII (CD16) triggers effective lysis of lymphoma cells. Br J Haematol 2004; 125:167 - 179; PMID: 15059139; http://dx.doi.org/10.1111/j.1365-2141.2004.04893.x
   PubMed Web of Science ®Google Scholar
• Benedict CA, MacKrell AJ, Anderson WF. Determination of the binding affinity of an anti-CD34 single-chain antibody using a novel, flow cytometry based assay. J Immunol Methods 1997; 201:223 - 231; PMID: 9050944; http://dx.doi.org/10.1016/S0022-1759(96)00227-X
   PubMed Web of Science ®Google Scholar
• Elsässer D, Valerius T, Repp R, Weiner GJ, Deo Y, Kalden JR, et al. HLA class II as potential target antigen on malignant B cells for therapy with bispecific antibodies in combination with granulocyte colony-stimulating factor. Blood 1996; 87:3803 - 3812; PMID: 8611706
   PubMed Web of Science ®Google Scholar