ABSTRACT Purpose: Investigation of safety, tolerability, pharmacokinetics, and anti-tumor activity of the Lewis Y-specific, fully humanized monoclonal antibody (mAb) IGN311 in patients with Lewis Y positive tumors in a Phase I clinical trial. Experimental Design: Twelve patients (pts) were enrolled in an open-label, uncontrolled, dose escalating Phase I study. Three pts received 50 mg, three pts 100 mg and six pts 200 mg IGN311 by i.v. infusion on days 1 and 15. Blood samples were taken immediately before infusion, and 0.5, 4, 8, 24 hours post infusion, as well as on days 3, 5 and 8 after the first and second infusion, respectively, and day 29. A final visit was scheduled for day 43. Results: No drug related adverse events were observed in the 50 mg and 100 mg dose groups. Three out of six patients in the 200 mg dose group showed drug related adverse reactions with nausea, vomiting and hypotension in one patient (NCI CTC grade 3) being the dose limiting toxicities. t1/2 of IGN311 was ~20 days after second infusion of IGN311. Sera of patients receiving IGN311 were capable of lysing Lewis Y positive tumor cells in vitro by both, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Circulating tumor cells found in the peripheral blood in two out of twelve pts prior to treatment were reduced after treatment to below the quantification limit of the detection method. None of the patients showed an increase in the number of disseminated tumor cells during treatment period. Conclusions: The good safety and PK profile, the biological activity regarding CDC and ADCC mediated tumor cell lysis, and the elimination of circulating tumor cells warrant further clinical investigation of IGN311.
Cite this paper
nullD. Oruzio, G. Waxenecker, C. Aulmann, B. Märkl, T. Wagner, G. 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 the Lewis Y Carbohydrate Specific Humanized Antibody IGN311," Journal of Cancer Therapy, Vol. 2 No. 5, 2011, pp. 760-771. doi: 10.4236/jct.2011.25102.
 M. Blaszczyk-Thurin, J. Thurin, O. Hindsgaul, K. A. Karlsson, Z. Steplewski and H. Koprowski, “Y and Blood Group B Type 2 Glycolipid Antigens Accumulate in a Human Gastric Carcinoma Cell Line as Detected by Monoclonal Antibody. Isolation and Characterization by Mass Spectrometry and NMR Spectroscopy,” Journal of Biological Chemistry, Vol. 262, No. 1, 1987, pp. 372-379.
 I. Hellstrom, H. J. Garrigues, U. Garrigues and K. E Hellstrom, “Highly Tumor-Reactive, Internalizing, Mouse Monoclonal Antibodies to Le(y)-Related Cell Surface Antigens,” Cancer Research, Vol. 50, No. 7, 1990, pp. 2183-2190.
 S. Zhang, H. S. Zhang, C. Cordon-Cardo, G. Ragupathi and P. O. Livingston, “Selection of Tumor Antigens as Targets for Immune Attack Using Immunohistochemistry: II. Blood Group-Related Antigens,” International Journal of Cancer, Vol. 73, No. 1, 1997, pp. 50-56.
 Y. S. Kim, M. Yuan, S. H. Itzkowitz, Q. B. Sun, T. Kaizu, A. Palekar, B. F. Trump and S. Hakomori, “Expression of LeY and Extended LeY Blood Group-Related Antigens in Human Malignant, Premalignant, and nonmalignant Colonic Tissues,” Cancer Research, Vol. 46, No. 11, 1986, 5985-5992.
 M. Dettke, G. Palfi and H. Loibner, “Activation-Dependent Expression of the Blood Group-Related Lewis Y Antigen on Peripheral Blood Granulocytes,” Journal of Leukocyte Biology, Vol. 68, No. 4, 2000, pp. 511-514.
 Z. Steplewski, M. Blaszczyk-Thurin, M. Lubeck, H. Loibner, D. Scholz and H. Koprowski, “Oligosaccharide Y Specific Monoclonal Antibody and Its Isotype Switch Variants,” Hybridoma, Vol. 9, No. 2, 1990, pp. 201-210.
 H. Inagaki, J. Sakamoto, H. Nakazato, H, A. E. Bishop and J. Yura, “Expression of Lewis(a), Lewis(b), and Sialated Lewis (a) Antigens in Early and Advanced Human Gastric Cancers,” Journal of Surgery Oncology, Vol. 44, No. 4, 1990, pp. 208-213. doi:10.1002/jso.2930440404
 J. Sakamoto, K. Furukawa, C. Cordon-Cardo, B. W. Yin, W. J. Rettig, H. F. Ottgen, L. J. Old and K. O. Lloyd, “Expression of Lewis a, Lewis b, X, and Y Blood Group Antigens in Human Colonic Tumors and Normal Tissue and in Human Tumor-Derived Cell Lines,” Cancer Research, Vol.46, No. 3, 1986, pp. 1553-1561.
 K. Murata, H. Egami, Y. Shibata, K. Sakamoto, A. Misumi and M. Ogawa, “Expression of Blood Group-Related Antigens, ABH, Lewis(a), Lewis(b), Lewis(x), Lewis(y), CA19-9, and CSLEX1 in Early Cancer, Intestinal Metaplasia, and Uninvolved Mucosa of the Stomach,” American Journal of Clinical Pathology, Vol. 98, No. 1, 1992, pp. 67-75.
 M. Miyake, T. Taki, S. Hitomi and S. Hakomori, “Correlation of Expression of H/Le(y)/Le(b) Antigens with Survival in Patients with Carcinoma of the Lung,” New England Journal of Medicine, Vol. 327, No. 1, 1992, pp. 14-18. doi:10.1056/NEJM199207023270103
 A. Larena, M. Vierbuchen, S. Schroder, A. Larena-Avellaneda, I. Hadshiew and R. Fischer, “Blood Group Antigen Expression in Papillary Carcinoma of the Thyroid Gland. An Immunohistochemical and Clinical Study of Expression of Lewis, ABO and Related Antigens,” Langenbecks Archiv fur Chirurgie, Vol. 381, No. 2, 1996, pp. 102-113.
 K. Steplewska-Mazur, A. Gabriel, W. Zajecki, M. Wylezol and M. Gluck, “Breast Cancer Progression and Expression of Blood Group-Related Tumor-Associated Antigens,” Hybridoma, Vol. 19, No. 2, 2000, pp. 129-133.
 H. Inufusa, Y. Nakatani, T. Adachi, T. Wakano, A. Nakajima, M. Nakamura, M. Suzuki, O. Ando, M. Kurimoto, M. Miyake, K. Shindo and M. Yasutomi, “Correlation of Prognosis of Breast Cancer Patients and Expression of Ley Which Acts as a Cofactor of Tumor Procoagulant,” International Journal of Oncology, Vol. 13, No. 3, 1998, pp. 481-487.
 Z. Madjd, T. Parsons, N. F. Watson, I. Spendlove, I. Ellis and L. G. Durrant, “High Expression of Lewis y/b Antigens Is Associated with decreased survival in Lymph Node Negative Breast Carcinomas,” Breast Cancer Research, Vol. 7, No. 5, 2005, pp. R780-R787.
 K. Kitamura, E. Stockert, P. Garin-Chesa, S. Welt, K. O. Lloyd, K. L. Armour, T. P. Wallace, W. J. Harris, F. J. Karr and L. J. Old, “Specificity Analysis of Blood Group Lewis-y (Le(y)) Antibodies Generated against Synthetic and Natural Le(y) Determinants,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 26, 1994, pp. 12957-12961.
 D. Scholz, M. Lubeck, H. Loibner, J. McDonald-Smith, Y. Kimoto, H. Koprowski and Z. Steplewski, “Biological Activity in the Human System of Isotype Variants of Oligosaccharide-Y-Specific Murine Monoclonal Antibodies,” Cancer Immunology, Immunotherapy, Vol. 33, No. 3, 1991, pp. 153-157. doi:10.1007/BF01756135
 Z. Steplewski, M. D. Lubeck, D. Scholz, H. Loibner, McDonald-Smith and H. Koprowski, “Tumor Cell Lysis and Tumor Growth Inhibition by the Isotype Variants of MAb BR55-2 Directed against Y Oligosaccharide,” In Vivo, Vol. 5, No. 2, 1991, pp. 79-83.
 G. Schlimok, K. Pantel, H. Loibner, I. Fackler-Schwalbe and G. Riethmüller, “ Reduction of Metastatic Carcinoma Cells in Bone Marrow by Intravenously Administered Monoclonal Antibody: Towards a Novel Surrogate Test to Monitor Adjuvant Therapies of Solid Tumours,” European Journal of Cancer, Vol. 31A, No. 11, 1995, pp. 1799-1803. doi:10.1016/0959-8049(95)00317-C
 R. A. Stahel, H. Lacroix, J. P. Sculier, R. Morant, J. Richner, E. Janzek, H. Loibner and H. Blythman, “Phase I/II Study of Monoclonal Antibody against Lewis Y Hapten in Relapsed Small-Cell Lung Cancer,” Annals of Oncology, Vol. 3, No. 4, 1992, pp. 319-320.
 G. Schlimok, G. Riethmuller, K. Pantel, et al., “Tumor Cell Cytotoxicity Induced in Patients by a Murine Monoclonal Antibody against the Lewis Y Antigen,” Proceeding of Annual Meeting of the American Society of Clinical Oncology, Vol. 10, 1991, pp. 212-214.
 I. Pastan, E. T. Lovelace, M. G. Gallo, A. V. Rutherford, J. L. Magnani and M. C. Willingham, “ Characterization of Monoclonal Antibodies B1 and B3 That React with Mucinous Adenocarcinomas,” Cancer Research, Vol. 51, No. 14, 1991, pp. 3781-3787.
 G. J. Schreiber, K. E. Hellstrom and I. Hellstrom, “An Unmodified Anticarcinoma Antibody, BR96, Localizes to and Inhibits the Outgrowth of Human Tumors in Nude Mice,” Cancer Research, Vol. 52, No. 12, 1992, pp. 3262-3266.
 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.
 H. Farhan, C. Schuster, M. Klinger, E. Weisz, G. Waxenecker, M. Schuster, V. Sexl, G. C. Mudde, M. Freissmuth and R. Kircheis, “Inhibition of Xenograft Tumor Growth and Down-Regulation of ErbB Receptors by an Antibody Directed against Lewis Y Antigen,” Journal of Pharmacology and Experimental Therapy, Vol. 319, No. 3, 2006, pp. 1459-1466. doi:10.1124/jpet.106.107318
 A. M. Scott, D. Geleick, M. Rubira, K. Clarke, E. C. Nice, F. E. Smyth, E. Stockert, E. C. Richards, F. J. Carr, W. J. Harris, K. L. Armour, J. Rood, A. Kypridis, V. Kronina, R. Murphy, F. T. Lee, Z. Liu, K. Kitamura, G. Ritter, K. Laughton, E. Hoffmann, A. W. Burgess and L. J. Old, “Construction, Production, and Characterization of Humanized Anti-Lewis Y Monoclonal Antibody 3S193 for Targeted Immunotherapy of Solid Tumors,” Cancer Research, Vol. 60, No. 12, 2000, pp. 3254-3261.
 A. M. Scott, N. Tebbutt, F. T. Lee, T. Cavicchiolo, Z. Liu, S. Gill, A. M. Poon, W. Hopkins, F. E. Smyth, C. Murone, D. MacGregor, A. T. Papenfuss, B. Chappell, T. H. Saunder, M. W. Brechbiel, I. D. Davies, R. Murphy, G. Chong, E. W. Hoffmann and L. J. Old, ”A Phase I Biodistribution and Pharmacokinetic Trial of Humanized Monoclonal Antibody Hu3s193 in Patients with Advanced Epithelial Cancers That Express the Lewis-Y Antigen,” Clinical Cancer Research, Vol. 13, No. 11, 2007, pp. 3286-3292. doi:10.1158/1078
 L. M. Krug, D. T. Milton, A. A. Jungbluth, L. C. Chen, E. Quaia, N. Pandit-Taskar, A. Nagel, J. Jones, M. G. Kris, R. Finn, P. Smith-Jones, A. M. Scott, L. Old and C. Divgi, “Targeting Lewis Y (Le(y)) in Small Cell Lung Cancer with a Humanized Monoclonal Antibody, hu3S193: A Pilot Trial Testing Two Dose Levels,” Journal Thorac Oncology, Vol. 2, No. 10, 2007, pp. 947-952.
 M. Cristofanilli, G. T. Budd, M. J. Elliset, A. Stopeck, J. Matera, M. C. Miller, J. M. Reuben, G. V. Doyle, W. J. Allard, L. W. Terstappen and D. F. Hayes, “Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer,” New England Journal of Med cine, Vol. 351, No. 8, 2004, pp. 781-791.
 M. Cristofanilli, D. F. Hayes, G. T. Budd, M. J. Ellis, A. Stopeck, J. M. Reuben, G. V. Doyle, J. Matera, W. J. Allard, M. C. Miller, H. A. Fritsche, G. N. Hortybagyi and L. W. Terstappen, “Circulating Tumor Cells: A Novel Prognostic Factor for Newly Diagnosed Metastatic Breast Cancer,” Journal of Clinical Oncology, Vol. 23, No. 7, 2005, pp. 1420-1430.
 S. Riethdorf, H. Fritsche, V. Müller, T. Rau, C. Schindlbeck, B. Rack, W. Janni, C. Coith, K. Beck, F. Janicke, S. Jackson, T. Gornet, M. Christofanilli and K. Pantel, “Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the Cell Search System,” Clinical Cancer Research, Vol. 13, No. 3, 2007, pp. 920-928.
 V. Muller, N. Stahmann, S. Riethdorf, T. Rau, T. Zabel, A. Goetz, F. Janicke and K. Pantel, “Circulating Tumor Cells in Breast Cancer: Correlation to Bone Marrow Micrometastases, Heterogeneous Response to Systemic Therapy and Low Proliferative Activity,” Clinical Cancer Research, Vol. 11, No. 10, 2005, pp. 3678-3685.
 M. Perkins, R. Theiler, S. Lunte and M. Jeschke, “Determination of the Origin of Charge Heterogeneity in a Murine Monoclonal Antibody,” Pharmaceutical Research, Vol. 17, No. 9, 2000, pp. 1110-1117.
 B. W. Cheung, L. L. Cartier, H. Q. Russlie, R. J. Sawchuk, “The Application of Sample Pooling Methods for Determining AUC, AUMC and Mean Residence Times in Pharmacokinetic Studies,” Fundamental & Clinical Pharmacology, Vol. 19, No. 3, 2005, pp. 347-354.
 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
 K. Tobinai, T. Igarashi, K. Itoh, Y. Kobayashi, M. Taniwaki, M. Ogura, T. Kinoshita, T. Hotta, K. Aikawa, K. Tsushita, A. Hiraoka, Y. Matsuno, S. Nakamura, S. Mori and Y. Ohashi, “Japanese Multicenter Phase II and Pharmacokinetic Study of Rituximab in Relapsed or Refractory Patients with Aggressive B-Cell Lymphoma,” Annals of Oncology, Vol. 15, No. 5, 2004, pp. 821-830.
 R. Bruno, C. B. Washington , J. F. Lu, G. Liebermann, L. Banken and P. Klein, “Population Pharmacokinetics of Trastuzumab In Patients With HER2+ Metastatic Breast Cancer,” Cancer Chemotherapy and Pharmacology, Vol. 56, No. 4, 2005, pp. 361-369.
 G. Ritter, L. S. Cohen, C. Williams Jr., E. C. Richard, 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.
 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, No. 4, 2004, pp. 948-955.
 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 of Clinical Oncology, Vol. 17, No. 9, 1999, pp. 2639-2648.
 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
 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, pp. 1087-1093.
 M. G. Krebs, R. Sloane, L. Priest, L. Lancashire, J. M. Hou, A. Greystoke, T. H. Ward, R. Ferraldeschi, A. Hughes, G. Clack, M. Ranson, C. Dive and F. H. Blackhall, “Evaluation and Prognostic Significance of Circulating Tumor Cells in Patients with Non-Small-Cell Lung Cancer,” Journal Clinical Oncology, Vol. 29, No. 12, 2011, pp. 1556-1563. doi:10.1200/JCO.2010.28.7045
 F. Tanaka, K. Yoneda, N. Kondo, M. Hashimoto, T. Ta- kuwa, S. Matsumoto, Y. Okumura, S. Rahman, N. Tsubota, T. Tsujimura, K. Kuribayashi, K. Fukuoka, T. Nakano and S. Hasegawa, “Circulating Tumor Cell as a Diagnostic Marker in Primary Lung Cancer,” Clinical Cancer Research, Vol. 15, No. 22, 2009, pp. 6980-6986. doi:10.1158/1078-0432.CCR-09-1095
 K. Pachmann, O. Camara, A. Kohlhase, C. Rabenstein, T. Kroll, I. B. Runnebaum and K. Hoeffken, “ Assessing the Efficacy of Targeted Therapy Using Circulating Epithelial Tumor Cells (CETC): The Example of SERM Therapy Monitoring as a Unique Tool to Individualize Therapy,” Journal Cancer Research Clinical Oncology, Vol. 137, No. 5, 2010, pp. 821-828.
 S. Maheswaran and D. A. Haber, “Circulating Tumor Cells: A Window into Cancer Biology and Metastasis,” Current Opinion Genetics Development, Vol. 20, No. 1, 2010, pp. 96-99. doi:10.1016/j.gde.2009.12.002
 M. Trzpis, P. M. J. McLaughlin, L. M. de Leij and M. C. Harmsen, “Epithelial Cell Adhesion Molecule. More than a Carcinoma Marker and Adhesion Molecule,” American Journal Pathology, Vol. 171, No. 2, 2007, pp. 386-395.
 E. A. Punnoose, S. K. Atwal, J. M. Spoerke, H. Savage, A. Pandita, R. F. Yeh, A. Pirzkall, B. M. Fine, L. C. Amler, D. S. Chen and M. R. Lackner, “Molecular Biomarker Analyses Using Circulating Tumor Cells,” PLoS One, Vol. 5, No. 9, 2010, p. e12517.
 E. Obermayr, F. Sanchez-Cabo, M. K. Tea, C. F. Singer, M. Krainer, M. B. Fischer, J. Sehouli, A. Reinthaller, R. Horvat, G. Heinze, D. Tong and R. Zeillinger, “Assessment of a Six Gene Panel for the Molecular Detection of Circulating Tumor Cells in the blood of Female Cancer Patients,” BMC Cancer, Vol. 10, pp. 666-672.