ABSTRACT Purpose: Detailed analysis of a patient with epithelial Lewis Y (LeY) positive cancer who received twice 50 mg of the humanized Lewis Y carbohydrate specific mAb IGN311 and developed a clinically significant human anti-human antibody (HAHA) response (Ab2). Results: Clinical stabilization of the disease was assigned to in this patient. The HAHA response consisted mainly of IgG1 and was found to be directed against the IGN311 binding site. Consistent with the induction of the HAHA response, CDC activity against Lewis Y positive target cells was completely abolished at day 8 and could not be restored by the second 50 mg infusion indicating complete neutralization of applied IGN311. The ADCC reactivity was also significantly reduced and anti-anti idiotype-specific antibodies (Ab3) were detectable at day 65. Conclusions: Induction of Ab3 antibodies should be considered as an additional factor influencing the efficacy of humanized antibodies. In this context, the potential threat of induced HAHA responses against therapeutic mAbs might have to be reconsidered because they might actually have also beneficial immunological long-term effects leading to an active immunization component induced by therapeutic antibodies.
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A. Nechansky, S. Stranner, O. Scheiber, N. Halanek and R. Kircheis, "Induction of Human Anti-Human Antibody Responses (Ab2) after Application of a Humanized Lewis Y Carbohydrate Specific Antibody (Ab1): Connection of Prolonged Disease Stabilization with Ab3 Induction?," Journal of Cancer Therapy, Vol. 3 No. 4, 2012, pp. 269-277. doi: 10.4236/jct.2012.34038.
 A. Nechansky and R. Kircheis, “Immunogenicity of Therapeutics: A Matter of Efficacy and Safety,” Expert Opinion Drug Discovery, Vol. 5, No. 11, 2010, pp. 1-13.
 M. B. Khazaeli, R .M. Conry and A. F. LoBuglio, “Human Immune Response to Monoclonal Antibodies,” Journal Immunotherapy Emphasis Tumor Immunology, 1994, Vol. 15, No. 1, pp. 42-52.
 J. E. Frodin, M. E. Faxas, B. Hagstrom, A. K. Lefvert, G. Masucci, B. Nilsson, M. Steinitz, P. Unger and H. Mellstedt, “Induction of Anti-Idiotypic (ab2) and Anti-Anti-Idiotypic (ab3) Antibodies in Patients Treated with the Mouse Monoclonal Antibody 17-1A (ab1). Relation to the Clinical Outcome—An Important Antitumoral Effector Function?” Hybridoma, Vol. 10, No. 4, 1991, pp. 421-431. doi:10.1089/hyb.1991.10.421
 H. Koprowski, D. Herlyn, M. Lubeck, E. DeFreitas and H. F. Sears, “Human Anti-Idiotype Antibodies in Cancer Patients: Is the Modulation of the Immune Response Beneficial for the Patient?” Proceedings of the National Academy of Sciences of the USA, Vol. 81, No. 1, 1994, pp. 216-219. doi:10.1073/pnas.81.1.216
 O. H. Brekke and I. Sandlie, “Therapeutic Antibodies for Human Diseases at the Dawn of the Twenty-First Century,” Nature Reviews Drug Discovery, Vol. 2, No. 3, 2003, pp. 52-62. doi:10.1038/nrd984
 A. Nechansky, “HAHA—Nothing to Laugh about. Measuring the Immunogenicity (Human Anti-Human Antibody Response) Induced by Humanized Monoclonal Antibodies Applying ELISA and SPR Technology,” Journal of Pharmaceutical and Biomedical Analysis, Vol. 51, No. 1, 2010, pp. 252-254. doi:10.1016/j.jpba.2009.07.013
 J. Fagerberg, A. L. Hjelm, P. Ragnhammar, J. E. Frodin, H. Wigzell and H. Mellstedt, “Tumor Regression in Monoclonal Antibody-Treated Patients Correlates with the Presence of Anti-Idiotype-Reactive T Lymphocytes,” Cancer Research, Vol. 55, No. 9, 1995, pp. 1824-1827.
 R. Gruber, L. J. van Haarlem, S. O. Warnaar, E. Holz and G. Riethmuller, “The Human Antimouse Immunoglobulin Response and the Anti-Idiotypic Network Have No Influence on Clinical Outcome in Patients with Minimal Residual Colorectal Cancer Treated with Monoclonal Antibody CO17-1A,” Cancer Research, Vol. 60, No. 7, 2000, pp. 1921-1926.
 J. Ma, J. Samuel, G. S. Kwon, A. A. Noujaim and R. Madiyalakan, “Induction of Anti-Idiotypic Humoral and Cellular Immune Responses by a Murine Monoclonal Antibody Recognizing the Ovarian Carcinoma Antigen CA125 Encapsulated in Biodegradable Microspheres,” Cancer Immunology Immunotherapy, Vol. 47, No. 1, 1998, pp. 13-20. doi:10.1007/s002620050499
 D. Herlyn, R. Somasundaram, W. Li and H. Maruyama, “Anti-Idiotype Cancer Vaccines: Past and Future,” Cancer Immunology Immunotherapy, Vol. 43, No. 2, 1996, pp. 65-76. doi:10.1007/s002620050305
 Y. Shoenfeld, “The Idiotypic Network in Autoimmunity: Antibodies That Bind,” Nature Medicine, Vol. 10, No. 1, 1994, pp. 17-18.
 Y. Shoenfeld, H. Amital, S. Ferrone and R.C. Kennedy, “Anti-Idiotypes and Their Application under Autoimmune, Neoplastic, and Infectious Conditions,” International Archives Allergy Immunology, Vol. 105, No. 3, 2005, pp. 211-223. doi:10.1159/000236760
 N. K. Jerne, “Towards a Network Theory of the Immune System,” Annual Immunology, Vol. 125, No. 1-2, 1974, pp. 373-389.
 D. V. Oruzio, G. Waxenecker, C. Aulmann, B. M?rkl, T. Wagner, G. C. Mudde, M. Schuster, N. Eller, A. Mayer, S. Stranner, G. Himmler, H. Loibner, G. Schlimok, R. Kircheis and A. Nechansky, “Phase I Dose Escalation Study with Le Y Carbohydrate Specific Humanized mAb IGN311,” Journal Cancer Therapy, Vol. 2, 2011, pp. 760-771. doi:10.4236/jct.2011.25102
 O. Szolar, S. Stranner, I. Zinoecker, G. C. Mudde, G. Himmler, G. Waxenecker and A. Nechansky, “Qualification and Application of a Surface Plasmon Resonance-Based Assay for Monitoring Potential HAHA Responses Induced after Passive Administration of a Humanized Anti Lewis-Y Antibody,” Journal of Pharmaceutical and Biomedical Analysis, Vol. 41, No. 4, 2006, pp. 1347-1353. doi:10.1016/j.jpba.2006.03.026
 G. Ritter, L. S. Cohen, C. Williams, E. C. Richards Jr., L. J. Old and S. Welt , “Serological Analysis of Human Anti-Human Antibody Responses in Colon Cancer Patients Treated with Repeated Doses of Humanized Monoclonal Antibody A33,” Cancer Research, Vol. 61, No. 18, 2001, pp. 6851-6859.
 M. S. Co, J. Baker, K. Bednarik, E. Janzek, W. Neruda, P. Mayer, R. Plot, B. Stumper, M. Vasquez, C. Queen and H. Loibner, “Humanized Anti-Lewis Y antibodies: In Vitro Properties and Pharmacokinetics in Rhesus Monkeys,” Cancer Research, Vol. 56, No. 5, 1996, pp. 1118-1125.
 M. Schuster, P. Umana, C. Ferrara, P. Brunker, C. Gerdes, G. Waxenecker, S. Wiederkum, C. Schwager, H. Loibner, G. Himmler and G. C. Mudde, “Improved Effector Functions of a Therapeutic Monoclonal Lewis Y-specific Antibody by Glycoform Engineering,” Cancer Research, Vol. 65, No. 17, 2005, pp.7934-7941.
 N. K. Cheung, I. Y. Cheung, A. Canete, S. J. Yeh, B. Kushner, M. A. Bonilla, G. Heller and S. M. Larson, “Antibody Response to Murine Anti-GD2 Monoclonal Antibodies: Correlation with Patient Survival,” Cancer Research, Vol. 54, 1994, pp. 2228-2233.
 J. Fagerberg, P. Ragnhammar, M. Liljefors, A. L. Hjelm, H. Mellstedt and J. E. Frodin, “Humoral Anti-Idiotypic and Anti-Anti-Idiotypic Immune Response in Cancer Patients Treated with Monoclonal Antibody 17-1A,” Cancer Immunology Immunotherapy, Vol. 42, No. 2, 1996, pp. 81-87. doi:10.1007/s002620050255
 A. V. Popov, X. Zou, J. Xian, I. C. Nicholson and M. Bruggemann, “A Human Immunoglobulin Lambda Locus Is Similarly Well Expressed in Mice and Humans,” Journal Experimental Medicine, Vol. 189, No. 10, 1999, pp. 1611-1620. doi:10.1084/jem.189.10.1611
 J. Fagerberg, J. E. Frodin, P. Ragnhammar, M. Steinitz, H. Wigzell and H. Mellstedt, “Induction of an Immune Network Cascade in Cancer Patients Treated with Monoclonal Antibodies (ab1). Is Induction of Anti-Idiotype Reactive T Cells (T3) of Importance for Tumor Response to mAb Therapy?” Cancer Immunol Immunotherapy, Vol. 38, 1994, pp. 149-159. doi:10.1007/s002620050048
 M. M. Uttenreuther-Fischer, J. A. Kruger and P. Fischer, “Molecular Characterization of the Anti-Idiotypic Immune Response of a Relapse-Free Neuroblastoma Patient Following Antibody Therapy: A Possible Vaccine against Tumors of Neuroectodermal Origin?” Journal Immunology, Vol. 176, No. 12, 2006, pp. 7775-7786.
 M. A. Cobleigh, C. L. Vogel, D. Tripathy, N. J. Robert, S. Scholl, L. Fehrenbacher, J. M. Wolter, V. Paton, S. Shak, G. Lieberman and D. J. Slamon, “Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed after Chemotherapy for Metastatic Disease,” Journal Clinical Oncology, Vol. 17, No. 9, 1999, pp. 2639-2648.
 G. Hale, P. Rebello, L. R. Brettman, C. Fegan, B. Kennedy, E. Kimby, M. Leach, J. Lundin, H. Mellstedt, P. Moreton, A. C. Rawstron, H. Waldmann, A. Osterborg and P. Hillmen, “Blood Concentrations of Alemtuzumab and Antiglobulin Responses in Patients with Chronic Lymphocytic Leukemia Following Intravenous or Subcutaneous Routes of Administration,” Blood, Vol. 104, 2004, pp. 948-955. doi:10.1182/blood-2004-02-0593
 S. Welt, G. Ritter, C. Williams Jr., L. S. Cohen, M. John, A. Jungbluth, E. A. Richards, L. J. Old and N. E. Kemeny, “Phase I Study of Anticolon Cancer Humanized Antibody A33,” Clinical Cancer Research, Vol. 9, No. 4, 2003, pp. 1338-1346.
 J. A. Lofgren, S. Dhandapani, J. J. Pennucci, C. M. Abbott, D. T. Mytych, A. Kaliyaperumal, S. J. Swanson and M. C. Mullenix, “Comparing ELISA and Surface Plasmon Resonance for Assessing Clinical Immunogenicity of Panitumumab,” Journal Immunology, Vol. 178, No. 11, 2007, pp. 7467-7472
 N.-K. V. Cheung, H. F. Guo, G. Heller and I. Y. Cheung, “Induction of Ab3 and Ab3’ Antibody Was Associated with Long-Term Survival after Anti-G(D2) Antibody Therapy of Stage 4 Neuroblastoma,” Clinical Cancer Research, Vol. 6, 2000, pp. 2653-2660.
 M. Klinger, H. Farhan, H. Just, H. Drobny, G. Himmler, G. C. Mudde, M. Freissmuth and V. Sexl, “Antibodies Directed against Lewis-Y Antigen Inhibit Signaling of Lewis-Y Modified ErbB Receptors,” Cancer Research, Vol. 64, No. 3, 2007, pp. 1087-1093.
 G. Sauter, R. Simon and K. Hillan, “Tissue Microarrays in Drug Discovery,” Nature Reviews Drug Discovery, Vol. 2, No. 12, 2003, pp. 962-972. doi:10.1038/nrd1254
 M. Schuster, A. Nechansky, H. Loibner and R. Kircheis, “Cancer Immunotherapy,” Biotechnol Journal, Vol. 1, No 2, 2006, pp. 138-147. doi:10.1002/biot.200500044