1,893
Views
26
CrossRef citations to date
0
Altmetric
Review

Antibody-siRNA conjugates: drugging the undruggable for anti-leukemic therapy

Pages 325-338 | Received 13 Apr 2016, Accepted 13 Dec 2016, Published online: 23 Dec 2016

References

  • Drexler HG, Minowada J. Lymphocytic leukemia and lymphomas. Immunol Ser. 1990;53:243–264.
  • Nambiar M, Kari V, Raghavan SC. Chromosomal translocations in cancer. Biochim Biophys Acta. 2008;1786:139–152.
  • Nussenzweig A, Nussenzweig MC. Origin of chromosomal translocations in lymphoid cancer. Cell. 2010;141:27–38.
  • Pui CH, Schrappe M, Ribeiro RC, et al. Childhood and adolescent lymphoid and myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2004;2004:118–145.
  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
  • Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.
  • Hoelzer D, Gokbuget N. Chemoimmunotherapy in acute lymphoblastic leukemia. Blood Rev. 2012;26:25–32.
  • Al-Hussaini M, DiPersio JF. Small molecule inhibitors in acute myeloid leukemia: from the bench to the clinic. Expert Rev Hematol. 2014;1:439–464.
  • Niewerth D, Jansen G, Assaraf YG, et al. Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Updat. 2015;18:18–35.
  • Brandwein JM, Hedley DW, Chow S, et al. A phase I/II study of imatinib plus reinduction therapy for c-kit-positive relapsed/refractory acute myeloid leukemia: inhibition of Akt activation correlates with complete response. Leukemia. 2011;25:945–952.
  • Yeung J, Esposito MT, Gandillet A, et al. beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell. 2010;18:606–618.
  • Rahman M, Hasan MR. Cancer metabolism and drug resistance. Metabolites. 2015;5:571–600.
  • Portell CA, Advani AS. Antibody therapy for acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2012;7:153–159.
  • Dujmovic D, Aurer I, Radman I, et al. Addition of rituximab to high-dose methotrexate-based chemotherapy improves survival of adults with Burkitt lymphoma/leukemia. Acta Haematol. 2012;127:115–117.
  • Weiner GJ. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer. 2015;15:361–370.
  • Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20:838–847.
  • Adair JR, Howard PW, Hartley JA, et al. Antibody-drug conjugates – a perfect synergy. Expert Opin Biol Ther. 2012;12:1191–1206.
  • Sliwkowski MX, Mellman I. Antibody therapeutics in cancer. Science. 2013;341:1192–1198.
  • Edwards AM, Isserlin R, Bader GD, et al. Too many roads not taken. Nature. 2011;470:163–165.
  • Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–811.
  • Ghildiyal M, Zamore PD. Small silencing RNAs: an expanding universe. Nat Rev Genet. 2009;10:94–108.
  • Uludag H, Landry B, Valencia-Serna J, et al. Current attempts to implement siRNA-based RNAi in leukemia models. Drug Discov Today. 2016;21:1412–1420.
  • Tyner JW, Walters DK, Willis SG, et al. RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia. Blood. 2008;111:2238–2245.
  • Zamore PD, Tuschl T, Sharp PA, et al. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell. 2000;101:25–33.
  • Martinez J, Patkaniowska A, Urlaub H, et al. Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell. 2002;110:563–574.
  • Joo MK, Yhee JY, Kim SH, et al. The potential and advances in RNAi therapy: chemical and structural modifications of siRNA molecules and use of biocompatible nanocarriers. J Control Release. 2014;193:113–121.
  • Wang T, Shigdar S, Shamaileh HA, et al. Challenges and opportunities for siRNA-based cancer treatment. Cancer Lett. 2016;17. Apr 1.
  • Sarisozen C, Salzano G, Torchilin VP. Lipid-based siRNA delivery systems: challenges, promises and solutions along the long journey. Curr Pharm Biotechnol. 2016;17:728–740.
  • Oh P, Li Y, Yu J, et al. Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature. 2004;429:629–635.
  • Zhao N, Qi J, Zeng Z, et al. Transfecting the hard-to-transfect lymphoma/leukemia cells using a simple cationic polymer nanocomplex. J Control Release. 2012;159:104–110.
  • He W, Bennett MJ, Luistro L, et al. Discovery of siRNA lipid nanoparticles to transfect suspension leukemia cells and provide in vivo delivery capability. Mol Ther. 2014;22:359–370.
  • Landry B, Valencia-Serna J, Gul-Uludag H, et al. Progress in RNAi-mediated molecular therapy of acute and chronic myeloid leukemia. Mol Ther Nucleic Acids. 2015;4:e240.
  • Yang Z, Yu B, Zhu J, et al. A microfluidic method to synthesize transferrin-lipid nanoparticles loaded with siRNA LOR-1284 for therapy of acute myeloid leukemia. Nanoscale. 2014;6:9742–9751.
  • Yang X, Koh CG, Liu S, et al. Transferrin receptor-targeted lipid nanoparticles for delivery of an antisense oligodeoxyribonucleotide against Bcl-2. Mol Pharm. 2009;6:221–230.
  • Koldehoff M, Elmaagacli AH. Therapeutic targeting of gene expression by siRNAs directed against BCR-ABL transcripts in a patient with imatinib-resistant chronic myeloid leukemia. Methods Mol Biol. 2009;487:451–466.
  • Ibrahim AM, Mansour IM, Wilson MM, et al. Study of survivin and X-linked inhibitor of apoptosis protein (XIAP) genes in acute myeloid leukemia (AML). Lab Hematol. 2012;18:1–10.
  • Erba HP, Sayar H, Juckett M, et al. Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML). Invest New Drugs. 2013;31:1023–1034.
  • Lacasse EC, Kandimalla ER, Winocour P, et al. Application of XIAP antisense to cancer and other proliferative disorders: development of AEG35156/GEM640. Ann N Y Acad Sci. 2005;1058:215–234.
  • Carter BZ, Mak DH, Morris SJ, et al. XIAP antisense oligonucleotide (AEG35156) achieves target knockdown and induces apoptosis preferentially in CD34+38- cells in a phase 1/2 study of patients with relapsed/refractory AML. Apoptosis. 2011;16:67–74.
  • Cortes J, Kantarjian H, Ball ED, et al. Phase 2 randomized study of p53 antisense oligonucleotide (cenersen) plus idarubicin with or without cytarabine in refractory and relapsed acute myeloid leukemia. Cancer. 2012;118:418–427.
  • Sapra P, Wang M, Bandaru R, et al. Down-modulation of survivin expression and inhibition of tumor growth in vivo by EZN-3042, a locked nucleic acid antisense oligonucleotide. Nucleosides Nucleotides Nucleic Acids. 2010;29:97–112.
  • Fisker N, Westergaard M,HF Hansen et al. Survivin mRNA antagonists using locked nucleic acid, potential for molecular cancer therapy. Nucleosides Nucleotides Nucleic Acids. 2007;26:1427–1430.
  • Park E, Gang EJ, Hsieh YT, et al. Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood. 2011;118:2191–2199.
  • Lanasa MC, Davis PH, Datto M, et al. Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:218–224.
  • Bienk K, Hvam ML, Pakula MM, et al. An albumin-mediated cholesterol design-based strategy for tuning siRNA pharmacokinetics and gene silencing. J Control Release. 2016;232:143–151.
  • Park J, Park J, Pei Y, et al. Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines. Adv Drug Deliv Rev. 2016;104:93–109.
  • Malek A, Merkel O, Fink L, et al. In vivo pharmacokinetics, tissue distribution and underlying mechanisms of various PEI(-PEG)/siRNA complexes. Toxicol Appl Pharmacol. 2009;236:97–108.
  • Zhou C, Zhang Y, Yu B, et al. Comparative cellular pharmacokinetics and pharmacodynamics of siRNA delivery by SPANosomes and by cationic liposomes. Nanomedicine. 2013;9:504–513.
  • Davis TA, Grillo-Lopez AJ, White CA, et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol. 2000;18:3135–3143.
  • Ai J, Advani A. Current status of antibody therapy in ALL. Br J Haematol. 2015;168:471–480.
  • James JS, Dubs G. FDA approves new kind of lymphoma treatment. Food and Drug Administration. AIDS Treat News. 1997;5:2–3.
  • Bassan R. Toward victory in adult ALL: blinatumomab joins. Blood. 2012;120:5094–5095.
  • La-Beck NM, Jean GW, C Huynh, et al. Immune checkpoint inhibitors: new insights and current place in cancer therapy. Pharmacotherapy. 2015;35:963–976.
  • Tedder TF, Streuli M, Schlossman SF, et al. Isolation and structure of a cDNA encoding the B1 (CD20) cell-surface antigen of human B lymphocytes. Proc Natl Acad Sci U S A. 1988;85:208–212.
  • Illidge TM. Obinutuzumab (GA101) – a different anti-CD20 antibody with great expectations. Expert Opin Biol Ther. 2012;12:543–545.
  • Tsai DE, Maillard I, Schuster SJ, et al. Use of ibritumomab tiuxetan anti-CD20 radioimmunotherapy in a non-Hodgkin’s lymphoma patient previously treated with a yttrium-90-labeled anti-CD22 monoclonal antibody. Clin Lymphoma. 2003;4:56–59.
  • Beers SA, Chan CH, James S, et al. Type II (tositumomab) anti-CD20 monoclonal antibody out performs type I (rituximab-like) reagents in B-cell depletion regardless of complement activation. Blood. 2008;112:4170–4177.
  • Osterborg A. Ofatumumab, a human anti-CD20 monoclonal antibody. Expert Opin Biol Ther. 2010;10:439–449.
  • Milani C, Castillo J. Veltuzumab, an anti-CD20 mAb for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and immune thrombocytopenic purpura. Curr Opin Mol Ther. 2009;11:200–207.
  • Genovese MC, Kaine JL, Lowenstein MB, et al. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study. Arthritis Rheum. 2008;58:2652–2661.
  • Sun LL, Ellerman D, Mathieu M, et al. Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies. Sci Transl Med. 2015;7:287–290.
  • Albanesi M, Daeron M. The interactions of therapeutic antibodies with Fc receptors. Immunol Lett. 2012;143:20–27.
  • Nadler LM, Ritz J, Hardy R, et al. A unique cell surface antigen identifying lymphoid malignancies of B cell origin. J Clin Invest. 1981;67:134–140.
  • Pawluczkowycz AW, Beurskens FJ, Beum PV, et al. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX. J Immunol. 2009;183:749–758.
  • Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520.
  • Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12:2031–2042.
  • Glennie MJ, French RR, Cragg MS, et al. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol. 2007;44:3823–3837.
  • Liebman HA, Saleh MN, Bussel JB, et al. Low-dose anti-CD20 veltuzumab given intravenously or subcutaneously is active in relapsed immune thrombocytopenia: a phase I study. Br J Haematol. 2013;162:693–701.
  • Reichert JM. Antibodies to watch in 2015. MAbs. 2015;7:1–8.
  • Ball ED, Davis RB, Griffin JD, et al. Prognostic value of lymphocyte surface markers in acute myeloid leukemia. Blood. 1991;77:2242–2250.
  • Ingle GS, Chan P, Elliott JM, et al. High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate. Br J Haematol. 2008;140:46–58.
  • Hong EE, Erickson H, Lutz RJ, et al. Design of coltuximab ravtansine, a cd19-targeting antibody-drug conjugate (ADC) for the treatment of b-cell malignancies: structure-activity relationships and preclinical evaluation. Mol Pharm. 2015;12:1703–1716.
  • Mehta A, Forero-Torres A. Development and integration of antibody-drug conjugate in non-Hodgkin lymphoma. Curr Oncol Rep. 2015;17:41.
  • Wu J, Fu J, Zhang M, et al. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 2015;8:104.
  • Suryadevara CM, Gedeon PC, Sanchez-Perez L, et al. Are BiTEs the “missing link” in cancer therapy?. Oncoimmunology. 2015;4:e1008339.
  • Haas C, Krinner E, Brischwein K, et al. Mode of cytotoxic action of T cell-engaging BiTE antibody MT110. Immunobiology. 2009;214:441–453.
  • Walker JA, Smith KG. CD22: an inhibitory enigma. Immunology. 2008;123:314–325.
  • Juweid M. Technology evaluation: epratuzumab, Immunomedics/Amgen. Curr Opin Mol Ther. 2003;5:192–198.
  • Awan FT, Hillmen P, Hellmann A, et al. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014;167:466–477.
  • De Masson A, Guitera P, Brice P, et al. Long-term efficacy and safety of alemtuzumab in advanced primary cutaneous T-cell lymphomas. Br J Dermatol. 2014;170:720–724.
  • Langley RG, Papp K, Bissonnette R, et al. Safety profile of intravenous and subcutaneous siplizumab, an anti-CD2 monoclonal antibody, for the treatment of plaque psoriasis: results of two randomized, double-blind, placebo-controlled studies. Int J Dermatol. 2010;49:818–828.
  • Malcolm SL, Smith EL, T Bourne, et al. A humanised mouse model of cytokine release: comparison of CD3-specific antibody fragments. J Immunol Methods. 2012;384:33–42.
  • d’Amore F, Radford J, Relander T, et al. Phase II trial of zanolimumab (HuMax-CD4) in relapsed or refractory non-cutaneous peripheral T cell lymphoma. Br J Haematol. 2010;150:565–573.
  • Janik JE, Morris JC, O’Mahony D, et al. 90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma. Proc Natl Acad Sci U S A. 2015;112:13045–13050.
  • Walter RB, Appelbaum FR, Tallman MS, et al. Shortcomings in the clinical evaluation of new drugs: acute myeloid leukemia as paradigm. Blood. 2010;116:2420–2428.
  • Kinstrie R, Copland M. Targeting chronic myeloid leukemia stem cells. Curr Hematol Malig Rep. 2013;8:14–21.
  • Bernstein ID. CD33 as a target for selective ablation of acute myeloid leukemia. Clin Lymphoma. 2002;2:S9–11.
  • Hamann PR, Hinman LM, Beyer CF, et al. An anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of Linker. Bioconjug Chem. 2002;13:40–46.
  • Stasi R. Gemtuzumab ozogamicin: an anti-CD33 immunoconjugate for the treatment of acute myeloid leukaemia. Expert Opin Biol Ther. 2008;8:527–540.
  • Raza A, Jurcic JG, Roboz GJ, et al. Complete remissions observed in acute myeloid leukemia following prolonged exposure to lintuzumab: a phase 1 trial. Leuk Lymphoma. 2009;50:1336–1344.
  • Sutherland MK, Yu C, Lewis TS, et al. Anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia. MAbs. 2009;1:481–490.
  • Sekeres MA, Lancet JE, Wood BL, et al. Randomized phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica. 2013;98:119–128.
  • Burnett AK, Hills RK, Hunter AE, et al. The addition of gemtuzumab ozogamicin to low-dose ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia. 2013;27:75–81.
  • Pagel JM, Hedin N, Subbiah K, et al. Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas. Blood. 2003;101:2340–2348.
  • Kletting P, Kull T, Bunjes D, et al. Radioimmunotherapy with anti-CD66 antibody: improving the biodistribution using a physiologically based pharmacokinetic model. J Nucl Med. 2010;51:484–491.
  • Chumsri S, Matsui W, Burger AM. Therapeutic implications of leukemic stem cell pathways. Clin Cancer Res. 2007;13:6549–6554.
  • Jin L, Lee EM, Ramshaw HS, 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.
  • Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade IN melanoma. Clin Ther. 2015;37:764–782.
  • Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480–489.
  • Aharonov A, Fuchs S, Stollar BD, et al. Immunogenicity and antigenic specificity of a glutaraldehyde cross-linked transfer RNA-protein conjugate. Eur J Biochem. 1974;42:73–79.
  • Mitra M, Kandalam M, Rangasamy J, et al. Novel epithelial cell adhesion molecule antibody conjugated polyethyleneimine-capped gold nanoparticles for enhanced and targeted small interfering RNA delivery to retinoblastoma cells. Mol Vis. 2013;19:1029–1038.
  • Ma Y, Kowolik CM, Swiderski PM, et al. Humanized Lewis-Y specific antibody based delivery of STAT3 siRNA. ACS Chem Biol. 2011;6:962–970.
  • Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925–932.
  • Cuellar TL, Barnes D, Nelson C, et al. Systematic evaluation of antibody-mediated siRNA delivery using an industrial platform of THIOMAB-siRNA conjugates. Nucleic Acids Res. 2015;43:1189–1203.
  • Sugo T, Terada M, Oikawa T, et al. Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release. 2016;237:1–13.
  • French RR. How to make bispecific antibodies. Methods Mol Med. 2000;40:333–339.
  • Rivera S, Yuan F. Critical issues in delivery of RNAi therapeutics in vivo. Curr Pharm Biotechnol. 2012;13:1279–1291.
  • Rothdiener M, Muller D, Castro PG, et al. Targeted delivery of siRNA to CD33-positive tumor cells with liposomal carrier systems. J Control Release. 2010;144:251–258.
  • Van Asbeck AH, Beyerle A, McNeill H, et al. Molecular parameters of siRNA – cell penetrating peptide nanocomplexes for efficient cellular delivery. ACS Nano. 2013;7:3797–3807.
  • Eguchi A, Meade BR, Chang YC, et al. Efficient siRNA delivery into primary cells by a peptide transduction domain-dsRNA binding domain fusion protein. Nat Biotechnol. 2009;27:567–571.
  • Vincent KJ, Zurini M. Current strategies in antibody engineering: fc engineering and pH-dependent antigen binding, bispecific antibodies and antibody drug conjugates. Biotechnol J. 2012;7:1444–1450.
  • Lu H, Wang D, Kazane S, et al. Site-specific antibody-polymer conjugates for siRNA delivery. J Am Chem Soc. 2013;135:13885–13891.
  • Dorner T, Shock A, Goldenberg DM, et al. The mechanistic impact of CD22 engagement with epratuzumab on B cell function: implications for the treatment of systemic lupus erythematosus. Autoimmun Rev. 2015. Jul 23;14.
  • Wu C, Ying H, Grinnell C, et al. Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat Biotechnol. 2007;25:1290–1297.
  • Williams AJ, Giese G, Persson J. Improved assembly of bispecific antibodies from knob and hole half-antibodies. Biotechnol Prog. 2015;31:1315–1322.
  • Beck A, Wurch T, Bailly C, et al. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol. 2010;10:345–352.
  • Rossi EA, Chang CH, TM Cardillo, et al. Optimization of multivalent bispecific antibodies and immunocytokines with improved in vivo properties. Bioconjug Chem. 2013;24:63–71.
  • Hinton PR, Xiong JM, Johlfs MG, et al. An engineered human IgG1 antibody with longer serum half-life. J Immunol. 2006;176:346–356.
  • Mosesson Y, Mills GB, Yarden Y. Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer. 2008;8:835–850.
  • Chiu SJ, Liu S, Perrotti D, et al. Efficient delivery of a Bcl-2-specific antisense oligodeoxyribonucleotide (G3139) via transferrin receptor-targeted liposomes. J Control Release. 2006;112:199–207.
  • Blum W, Garzon R, Klisovic RB, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010;107:7473–7478.
  • Niewoehner J, Bohrmann B, Collin L, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014;81:49–60.
  • Jackson AL, Linsley PS. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discov. 2010;9:57–67.
  • Wu H, Pfarr DS, Johnson S, et al. Development of motavizumab, an ultra-potent antibody for the prevention of respiratory syncytial virus infection in the upper and lower respiratory tract. J Mol Biol. 2007;368:652–665.
  • Hotzel I, Theil FP, Bernstein LJ, et al. A strategy for risk mitigation of antibodies with fast clearance. MAbs. 2012;4:753–760.
  • Bumbaca D, Wong A, Drake E, et al. Highly specific off-target binding identified and eliminated during the humanization of an antibody against FGF receptor 4. MAbs. 2011;3:376–386.
  • Feyen O, Lueking A, Kowald A, et al. Off-target activity of TNF-alpha inhibitors characterized by protein biochips. Anal Bioanal Chem. 2008;391:1713–1720.
  • Ehninger A, Kramer M, Rollig C, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J. 2014;4:e218.
  • Schubert I, Kellner C, Stein C, 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.
  • Donaldson JM, Kari C, Fragoso RC, et al. Design and development of masked therapeutic antibodies to limit off-target effects: application to anti-EGFR antibodies. Cancer Biol Ther. 2009;8:2147–2152.
  • Wang Y, Santos M, Guttman A. Comparative core fucosylation analysis of some major therapeutic antibody N-glycans by direct infusion ESI-MS and CE-LIF detection. J Sep Sci. 2013;36:2862–2867.
  • Gorovits B, Krinos-Fiorotti C. Proposed mechanism of off-target toxicity for antibody-drug conjugates driven by mannose receptor uptake. Cancer Immunol Immunother. 2013;62:217–223.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.