Safety and Therapeutic Efficacy of the Lewis Y Carbohydrate Specific Humanized Antibody MB311 in Patients with Malignant Effusion


Purpose: Investigation of safety and tolerability as well as therapeutic efficacy of the LeY specific humanized mAb MB311 in cancer pts with malignant effusions in a Phase II clinical trial. Experimental Design: An openlabel, single treatment arm, uncontrolled study with MB311 (100 mg per dose, intravenous infusion on day 1 and 7) in pts with malignant effusion (ascites or pleural effusion) was conducted with the primary objective to examine safety and tolerability as well as pharmacokinetics. Secondary objectives were assessment of pharmacodynamics, volumetric measurement of the malignant effusion and obtaining data for several immunological parameters. Results: Five pts (2 pts with gastric cancer and malignant ascites, 3 pts with breast cancer and malignant pleural effusion/ascites) have completed the study. MB311 was well tolerated with only two pts showing the easily manageable side effects nausea, vomiting (up to grade 2) and one episode of skin rash (grade 2) after the first application. Data of 4 pts were available for evaluating immunologic results and efficacy. In all pts significant levels of MB311 could be detected in the systemic blood circulation and the effusion leading to increased infiltration of CD45 positive immune cells (4/5 pts) and resulting in a reduction of tumor cell counts as detected by immunocytochemistry of effusion samples in 3/5 pts). Most interestingly, the pt with the highest LeY positive tumor showed a significant reduction of effusion volume after treatment—this decrease was also evident for Her2/neu positive tumor cells which were dramatically reduced after MB311 treatment in this breast cancer pt. Conclusion: MB311 was well tolerated in patients with malignant effusions, permeated into malignant effusion and attracted immune cells leading to decreased tumor cell counts in the effusion. In the case of strong LeY expression of malignant cells in the effusion a pronounced decrease in LeY, EpCAM and Her2/neu positive tumor cells and a significant reduction of the effusion volume could be demonstrated.

Share and Cite:

T. Bauernhofer, H. Samonigg, P. Regitnik, W. Weitzer, B. Lileg, G. Waxenecker, S. Wiederkum, M. Kainer, M. Schuster, H. Loibner, M. Fido, R. Kircheis and A. Nechansky, "Safety and Therapeutic Efficacy of the Lewis Y Carbohydrate Specific Humanized Antibody MB311 in Patients with Malignant Effusion," Journal of Cancer Therapy, Vol. 5 No. 1, 2014, pp. 28-37. doi: 10.4236/jct.2014.51004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. M. Scott and S. Welt, “Antibody-Based Immunological Therapies,” Current Opinion in Immunology, Vol. 9, No. 5, 1997, pp. 717-722.
[2] I. Hellstrom, H. J. Garrigues, U. Garrigues, et al., “Highly Tumor-Reactive, Internalizing, Mouse Monoclonal Antibodies to Le(y)-Related Cell Surface Antigens,” Cancer Research, Vol. 50, No. 7, 1990, pp. 2183-2190.
[3] S. Zhang, H. S. Zhang, C. Cordon-Cardo, et al., “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. 73:1<50::AID-IJC9>3.0.CO;2-0
[4] Y. S. Kim, M. Yuan, I. S. Htzkowitz, et al., “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, pp. 5985-5992.
[5] 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.
[6] Z. Steplewski, M. Blaszczyk-Thurin, M. Lubeck, et al., “Oligosaccharide Y Specific Monoclonal Antibody and Its Isotype Switch Variants,” Hybridoma, Vol. 9, No. 2, 1990, pp. 201-210. 1089/hyb.1990.9.201
[7] H. Inagaki, J. Sakamoto, H. Nakazato, et al., “Expression of Lewis(a), Lewis(b), and Sialated Lewis(a) Antigens in Early and Advanced Human Gastric Cancers,” Journal of Surgical Oncology, Vol. 44, No. 4, 1990, pp. 208-213.
[8] J. Sakamoto, K. Furukawa, C. Cordon-Cardo, et al., “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.
[9] K. Murata, H. Egami, Y. Shibata, et al., “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.
[10] M. Miyake, T. Taki, S. Hitomi, et al., “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.
[11] A. Larena, M. Vierbuchen, S. Schroder, et al., “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 für Chirurgie, Vol. 381, No. 2, 1996, pp. 102-113.
[12] K. Steplewska-Mazur, A. Gabriel, W. Zajecki, et al., “Breast Cancer Progression and Expression of Blood Group-Related Tumor-Associated Antigens,” Hybridoma, Vol. 19, No. 2, 2000, pp. 129-133.
[13] H. Inufusa, Y. Nakatani, T. Adachi, et al., “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.
[14] Z. Madjd, T. Parsons, N. F. Watson, et al., “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. R780R787.
[15] K. Kitamura, E. Stockert, P. Garin-Chesa, et al., “ 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.
[16] D. Scholz, M. Lubeck, H. Loibner, et al., “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.
[17] Z. Steplewski, M. D. Lubeck, D. Scholz, et al., “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.
[18] G. Schlimok, K. Pantel, H. Loibner, et al., “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.
[19] R. A. Stahel, H. Lacroix, J. P. Sculier, et al., “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.
[20] G. Schlimok, G. Riethmüller, K. Pantel, et al., “Tumor Cell Cytotoxicity Induced in Patients by a Murine Monoclonal Antibody against the Lewis Y Antigen,” Annual Meeting of the American Society of Clinical Oncology, 1991.
[21] I. Pastan, E. T. Lovelace, M. G. Gallo, et al., “Characterization of Monoclonal Antibodies B1 and B3 That React with Mucinous Adenocarcinomas,” Cancer Research, Vol. 51, No. 14, 1991, pp. 3781-3787.
[22] G. J. Schreiber, K. E. Hellstr?m and I. Hellstr?m, “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.
[23] M. S. Co, J. Baker, K. Bednarik, et al., “Humanized AntiLewis Y Antibodies: In Vitro Properties and Pharmacokinetics in Rhesus Monkeys,” Cancer Research, Vol. 56, No. 5, 1996, pp. 1118-1125.
[24] H. Farhan, C. Schuster, M. Klinger, et al., “Inhibition of Xenograft Tumor Growth and Down-Regulation of ErbB Receptors by an Antibody Directed against Lewis Y Antigen,” Journal of Pharmacology and Experimental Therapeutics, Vol. 319, No. 3, 2006, pp. 1459-1466. 106.107318
[25] A. M. Scott, D. Geleick, M. Rubira, et al., “Construction, Production, and Characterization of Humanized AntiLewis Y Monoclonal Antibody 3S193 for Targeted Immunotherapy of Solid Tumors,” Cancer Research, Vol. 60, No. 12, 2000, pp. 3254-3261.
[26] A. M. Scott, N. Tebbutt, F. T. Lee, et al, “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.
[27] L. M. Krug, D. T. Milton, A. A. Jungbluth, et al., “Targeting Lewis Y (Le(y)) in Small Cell Lung Cancer with a Humanized Monoclonal Antibody, hu3S193: A Pilot Trial Testing Two Dose Levels,” Journal of Thoracic Oncology, Vol. 2, No. 10, 2007, pp. 947-952. 60dcc
[28] D. V. Oruzio, G. Waxenecker, C. Aulmann, B. M?rkl, T. Wagner, 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 LeY Specific Humanized Mab IGN311,” Journal of Cancer Therapy, Vol. 2, No. 5, 2011, pp. 760-771.
[29] 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.
[30] 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, 2004, pp. 1087-1093.
[31] G. Schlimok, K. Pantel, H. Loibner, et al., “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. 31, No. 11, 1995, pp 1799-1803.
[32] M. Cristofanilli, D. F. Hayes, G. T. Budd, et al., “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.
[33] S. Riethdorf, H. Fritsche, V. Müller, et al., “Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System,” Clinical Cancer Research, Vol. 13, No. 3, 2007, pp. 920-928.
[34] V. Müller, N. Stahmann, S. Riethdorf, et al., “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. 1158/1078-0432.CCR-04-2469
[35] M. G. Krebs, R. Sloane, L. Priest, et al., “Evaluation and Prognostic Significance of Circulating Tumor Cells in Patients with Non-Small-Cell Lung Cancer,” Journal of Clinical Oncology, Vol. 29, No. 12, 2011, pp. 1556-1563.
[36] F. Tanaka, K. Yoneda, N. Kondo, et al., “Circulating Tumor Cell as a Diagnostic Marker in Primary Lung Cancer,” Clinical Cancer Research, Vol. 15, No. 22, 2009, pp. 6980-6986. 1158/1078-0432.CCR-09-1095
[37] O. Szolar, S. Stranner, I. Zinoecker, et al., “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.
[38] M. Schuster, A. Nechansky and R. Kircheis, “Cancer Immunotherapy,” Biotechnology Journal, Vol. 1, No. 2, 2006, pp. 138-147.
[39] M. M. Heiss, P. Murawa, P. Koralewski, 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,” International Journal of Cancer, Vol. 127, No. 9, 2010, pp. 2209-2221.
[40] M. M. Heiss, M. A. Strohlein, M. Jager, R. Kimmig, A. Burges, A. Schoberth, K. W. Jauch, F. W. Schildberg and H. Lindhofer, “Immunotherapy of Malignant Ascites with Trifunctional Antibodies,” International Journal of Cancer, Vol. 117, No. 3, 2005, pp. 435-443. ijc.21165
[41] F. Li, B. Lin, Y. Hao, Y. Li, J. Liu, J. Cong, L. Zhu, Q. Liu and S. Zhang, “Lewis Y Promotes Growth and Adhesion of Ovarian Carcinoma-Derived RMG-I Cells by Upregulating Growth Factors,” International Journal of Molecular Sciences, Vol. 11, No. 10, 2010, pp. 3748-3759. ijms11103748
[42] J. A. Westwood, W. K. Murray, M. Trivett, et al., “The Lewis-Y Carbohydrate Antigen Is Expressed by Many Human Tumors and Can Serve as a Target for Genetically Redirected T Cells Despite the Presence of Soluble Antigen in Serum,” Journal of Immunotherapy, Vol. 32, No. 3, 2009, pp. 292-301.
[43] X. F. Wen, G. Yang, W. Mao, A. Thornton, J. Liu, R. C. Bast Jr. and X. F. Le, “HER2 Signaling Modulates the Equilibrium between Proand Antiangiogenic Factors via Distinct Pathways: Implications for HER2-Targeted Antibody Therapy,” Oncogene, Vol. 25, No. 52, 2006, pp. 6986-6996. 1038/sj.onc.1209685
[44] A. Nechansky, M. Schuster, W. Jost, P. Siegl, S. Wiederkum, G. Gorr and R. Kircheis, “Compensation of Endogenous IgG Mediated Inhibition of Antibody-Dependent Cellular Cytotoxicity by Glyco-Engineering of Therapeutic Antibodies,” Molecular Immunology, Vol. 44, No. 7, 2007, pp. 1826-1828.
[45] R. Kircheis, N. Halanek, M. Mayer, K. Hajszan, W. Jost, F. Altmann, G. Gorr and A. Nechansky, “Correlation of ADCC with Cytokine Release Induced by the Stably Expressed Glyco-Engineered Humanized Lewis Y Specific Monoclonal Antibody MB314,” MAbs, Vol. 4, No. 4, 2012, pp. 532-541.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.