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European Journal of Nanomedicine

Editor-in-Chief: Hunziker, Patrick / Mollenhauer, Jan

Managing Editor: Löffler, Beat / Salieb-Beugelaar, Georgette

Editorial Board: Alexiou, Christoph / Balogh, Lajos / Barenholz, Yechezkel / Dawson, Kenneth / Fadeel, Bengt / Husseini, Ghaleb / Krol, Silke / Lee, Dong Soo / Lehr, Claus-Michael / Mangge, Harald / Müller, Bert / Peer, Dan / Scoles, Giacinto / Serruys, Patrick / Schwartz, Simo / Szebeni, Janos

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Variable association of complement activation by rituximab and paclitaxel in cancer patients in vivo and in their screening serum in vitro with clinical manifestations of hypersensitivity: a pilot study

Gergely Tibor Kozma
  • Corresponding author
  • Nanomedicine Research and Education Center, Semmelweis University, Budapest, Hungary
  • SeroScience Ltd, Budapest Hungary
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Tamás Mészáros
  • Nanomedicine Research and Education Center, Semmelweis University, Budapest, Hungary
  • SeroScience Ltd, Budapest Hungary
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Zsóka Weiszhár
  • Nanomedicine Research and Education Center, Semmelweis University, Budapest, Hungary
  • SeroScience Ltd, Budapest Hungary
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Tamás Schneider / András Rosta / Rudolf Urbanics
  • Nanomedicine Research and Education Center, Semmelweis University, Budapest, Hungary
  • SeroScience Ltd, Budapest Hungary
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ László Rosivall
  • SeroScience Ltd, Budapest Hungary
  • Institute of Pathophysiology, Semmelweis University, Budapest, Hungary
  • International Nephrology Research and Training Center, Semmelweis University, Budapest, Hungary
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ János Szebeni
  • Nanomedicine Research and Education Center, Semmelweis University, Budapest, Hungary
  • SeroScience Ltd, Budapest Hungary
  • Institute of Pathophysiology, Semmelweis University, Budapest, Hungary
  • Department of Nanobiotechnology and Regenerative Medicine, Miskolc University, Miskolc, Hungary
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-10-17 | DOI: https://doi.org/10.1515/ejnm-2015-0026


To explore the role of complement (C) activation in the hypersensitivity reactions (HSRs) to some anticancer drugs, as well as the use of the C activation biomarkers (Cbiom) C3a, C5a and SC5b-9 in the prediction of HSRs, we measured these Cbiom in plasma samples of cancer patients during infusion therapy, and in their pretreatment (screening) serum incubated with these drugs in vitro. Rituximab and paclitaxel caused mild to severe HSRs in 8/20 and 4/4 patients, respectively, which were associated with rises or falls of plasma and/or serum Cbioms. Among these changes, a rise of C3a in the plasma of 8/8 rituximab reactors and strong rises of Cbioms in the screening sera of all paclitaxel patents were most prominent. However, in the case of rituximab, significant Cbiom changes were also seen in nonreactors, while Cbiom changes were absent in the screening serum. Thus, C activation may be causally involved, but it is not rate limiting factor to HSRs to rituximab. Additional initial data in this study suggest that a whole blood assay using hirudin is more sensitive to C activation by rituximab than the serum test; that trastuzumab and docetaxel also cause HSRs with changes of Cbioms, and that an anti-paclitaxel antibody (ADA) ELISA may be useful as a predictor test for HSRs to Paclitaxel.

Keywords: anaphylaxis; anti-drug antibodies; cancer therapy; hypersensitivity reactions; immunogenicity; nanomedicines


  • 1.

    Pichler WJ. Adverse side-effects to biological agents. Allergy 2006;61:912–20.CrossrefGoogle Scholar

  • 2.

    Castells MC, Tennant NM, Sloane DE, Hsu FI, Barrett NA, Hong DI, et al. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122:574–80.CrossrefGoogle Scholar

  • 3.

    Castells MC. Hypersensitivity to antineoplastic agents. Curr Pharm Des 2008;14:2892–901.CrossrefGoogle Scholar

  • 4.

    Vultaggio A, Matucci A, Nencini F, Pratesi S, Parronchi P, Rossi O, et al. Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions. Allergy 2010;65:657–61.CrossrefGoogle Scholar

  • 5.

    Maggi E, Vultaggio A, Matucci A. Acute infusion reactions induced by monoclonal antibody therapy. Expert Rev Clin Immunol 2011;7:55–63.CrossrefGoogle Scholar

  • 6.

    Szebeni J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol Immunol 2014;61:163–73.CrossrefGoogle Scholar

  • 7.

    Szebeni J, Fontana JL, Wassef NM, Mongan PD, Morse DS, Dobbins DE, et al. Hemodynamic changes induced by liposomes and liposome-encapsulated hemoglobin in pigs: a model for pseudoallergic cardiopulmonary reactions to liposomes. Role of complement and inhibition by soluble CR1 and anti-C5a antibody. Circulation 1999;99:2302–9.CrossrefGoogle Scholar

  • 8.

    Szebeni J. Complement activation-related pseudoallergy: a new class of drug-induced immune toxicity. Toxicology 2005;216: 106–21.CrossrefGoogle Scholar

  • 9.

    Szebeni J. Complement activation-related pseudoallergy caused by liposomes, micellar carriers of intravenous drugs and radiocontrast agents. Crit Rev Ther Drug Carr Syst 2001;18:567–606.CrossrefGoogle Scholar

  • 10.

    Szebeni J. Complement activation-related pseudoallergy: mechanism of anaphylactoid reactions to drug carriers and radiocontrast agents. In: Szebeni J, editor. The complement system: novel roles in health and disease. Boston: Kluwer, 2004:399–440.Google Scholar

  • 11.

    Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003;98:1315–24.CrossrefGoogle Scholar

  • 12.

    Duburque C, Lelong J, Iacob R, Seddik M, Desreumaux P, Fournier C, et al. Successful induction of tolerance to infliximab in patients with Crohn’s disease and prior severe infusion reactions. Aliment Pharmacol Ther 2006;24:851–8.CrossrefGoogle Scholar

  • 13.

    Kang SP, Saif MW. Infusion-Related and hypersensitivity reactions of monoclonal antibodies used to treat colorectal cancer: Iidentification, prevention and management. J Support Oncol 2007;5:451–7.Google Scholar

  • 14.

    Brennan PJ, Rodriguez BT, Hsu FI, Sloane DE, Castells MC. Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment. J Allergy Clin Immunol 2009;124:1259–66.Google Scholar

  • 15.

    Vultaggio A, Maggi E, Matucci A. Immediate adverse reactions to biologicals: from pathogenic mechanisms to prophylactic management. Curr Opin Allergy Clin Immunol 2011;11:262–8.CrossrefGoogle Scholar

  • 16.

    Hong DI, Bankova L, Cahill KN, Kyin T, Castells MC. Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies. Expert Rev Clin Immunol 2012;8:43–52.CrossrefGoogle Scholar

  • 17.

    Sharma D, Chelvi TP, Kaur J, Chakravorty K, De TK, Maitra A, et al. Novel Taxol formulation: polyvinylpyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy. Oncol Res 1996;8:281–6.Google Scholar

  • 18.

    Preston NJ. Paclitaxel (Taxol)–a guide to administration. Eur J Cancer Care (Engl) 1996;5:147–52.CrossrefGoogle Scholar

  • 19.

    Paul DM, Garrett AM, Meshad M, DeVore RD, Porter LL, Johnson DH. Paclitaxel and 5-fluorouracil in metastatic breast cancer: the US experience. Semin Oncol 1996;23(1 Suppl 1): 48–52.Google Scholar

  • 20.

    Hajek R, Vorlicek J, Slavik M. Paclitaxel (Taxol): a review of its antitumor activity in clinical studies Minireview. Neoplasma 1996;43:141–54.Google Scholar

  • 21.

    Hajek R. [Paclitaxel (Taxol)]. Cas Lek Cesk 1996;135:393–6.Google Scholar

  • 22.

    Blom R, Palm N, Simonsen E. Paclitaxel (Taxol) monotherapy in the treatment of progressive and recurrent ovarian carcinoma after platinum-based chemotherapy. Acta Oncol 1996;35:733–6.CrossrefGoogle Scholar

  • 23.

    Piccart MJ, Gore M, Ten Bokkel Huinink W, Van Oosterom A, Verweij J, Wanders J, et al. Docetaxel: an active new drug for treatment of advanced epithelial ovarian cancer. J Natl Cancer I 1995;87:676–81.CrossrefGoogle Scholar

  • 24.

    Fumoleau P, Perrocheau G, Maugard-Louboutin C, Lemevel B. [Paclitaxel (Taxol) and docetaxel (Taxotere): results of phase II trials in monochemotherapy]. Bull Cancer 1995;82:629–36.Google Scholar

  • 25.

    Francis PA, Kris MG, Rigas JR, Grant SC, Miller VA. Paclitaxel (Taxol) and docetaxel (Taxotere): active chemotherapeutic agents in lung cancer. Lung Cancer 1995;12(Suppl 1):S163–72.CrossrefGoogle Scholar

  • 26.

    Uziely B, Jeffers S, Muggia F. Low doses of dexamethasone protect against paclitaxel (Taxol)-related hypersensitivity reactions following cycle 1. Ann Oncol 1994;5:474.Google Scholar

  • 27.

    Greco FA, Hainsworth JD. Paclitaxel (Taxol): phase I/II trial comparing 1-hour infusion schedules. Semin Oncol 1994; 21(5 Suppl 8):3–8.Google Scholar

  • 28.

    Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. Clinical toxicities encountered with paclitaxel (Taxol). Seminars in Oncology 1993;20(4 Suppl 3):1–15.Google Scholar

  • 29.

    Peereboom DM, Donehower RC, Eisenhauer EA, McGuire WP, Onetto N, Hubbard JL, et al. Successful re-treatment with taxol after major hypersensitivity reactions. J Clin Oncol 1993;11:885–90.Google Scholar

  • 30.

    Onetto N, Canetta R, Winograd B, Catane R, Dougan M, Grechko J, et al. Overview of Taxol safety. J Natl Cancer Inst Monogr 1993:131–9.Google Scholar

  • 31.

    Brown T, Havlin K, Weiss G, Cagnola J, Koeller J, Kuhn J, et al. A phase I trial of taxol given by a 6-hour intravenous infusion. J Clin Oncol 1991;9:1261–7.Google Scholar

  • 32.

    Weiss RB, Donehower RC, Wiernik PH, Ohnuma T, Gralla RJ, Trump DL, et al. Hypersensitivity reactions from Taxol. J Clin Oncol 1990;8:1263–8.Google Scholar

  • 33.

    Weiss RB, Baker JR. Hypersensitivity reactions from antineoplastic agents. Cancer Metastasis Rev 1987;6:413–32.CrossrefGoogle Scholar

  • 34.

    Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients. A meta-analysis of prospective studies. J Am Med Assoc 1998;279:1200–5.CrossrefGoogle Scholar

  • 35.

    Adkinson NF, Essayan D, Gruchalla R, Haggerty H, Kawabata T, Sandler JD, et al. Task force report: future research needs for the prevention and management of immune-mediated drug hypersensitivity reactions. J Allergy Clin Immunol 2002;109:S461–78.CrossrefGoogle Scholar

  • 36.

    Szebeni J. Hemocompatibility testing for nanomedicines and biologicals: predictive assays for complement mediated infusion reactions. Eur J Nanomed 2012;5:33–53.Google Scholar

  • 37.

    Szebeni J, Muggia FM, Alving CR. Complement activation by Cremophor EL as a possible contributor to hypersensitivity to paclitaxel: an in vitro study. J Natl Cancer I 1998;90:300–6.CrossrefGoogle Scholar

  • 38.

    Szebeni J, Baranyi L, Savay S, Götze O, Alving CR, Bünger R, et al. Complement activation during hemorrhagic shock and resuscitation in swine. Shock 2003;20:347–55.CrossrefGoogle Scholar

  • 39.

    Weiszhár Z, Czúcz J, Révész C, Rosivall L, Szebeni J, Rozsnyay Z. Complement activation by polyethoxylated pharmaceutical surfactants: Cremophor-EL, Tween-80 and Tween-20. Eur J Pharm 2012;45:492–8.Google Scholar

  • 40.

    Chanan-Khan A, Szebeni J, Savay S, Liebes L, Rafique NM, Alving CR, et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions. Ann Oncol 2003;14:1430–7.CrossrefGoogle Scholar

  • 41.

    Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:371–6.CrossrefGoogle Scholar

  • 42.

    Van Beers MM, Bardor M. Minimizing immunogenicity of biopharmaceuticals by controlling critical quality attributes of proteins. Biotechnol J 2012;7:1473–84.CrossrefGoogle Scholar

  • 43.

    Szebeni J, Jiskoot W. Immunological issues with nanomedicines: immunogenicity, hypersensitivity, accelerated clearance and immune suppression. In: Torchillin V, editor. Handbook of nanobiomedical research. Singapore: World Scientific, 2014:45–73.Google Scholar

  • 44.

    Pazdur R, Kudelka AP, Kavanagh JJ, Cohen PR, Raber MN. The taxoids: paclitaxel (Taxol) and docetaxel (Taxotere). Cancer Treat Rev 1993;19:351–86.CrossrefGoogle Scholar

  • 45.

    Tsavaris NB, Kosmas C. Risk of severe acute hypersensitivity reactions after rapid paclitaxel infusion of less than 1-h duration. Cancer Chemoth Pharm 1998;42:509–11.CrossrefGoogle Scholar

  • 46.

    Szebeni J, Alving CR, Savay S, Barenholz Y, Priev A, Danino D, et al. Formation of complement-activating particles in aqueous solutions of Taxol: possible role in hypersensitivity reactions. Int Immunopharmacol 2001;1:721–35.CrossrefGoogle Scholar

  • 47.

    van der Kolk LE, Grillo-López AJ, Baars JW, Hack CE, van Oers MH. Complement activation plays a key role in the side-effects of rituximab treatment. Brit J Haematol 2001;115:807–11.CrossrefGoogle Scholar

  • 48.

    Szebeni J, Muggia F, Gabizon A, Barenholz Y. Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliver Rev 2011;63:1020–30.CrossrefGoogle Scholar

  • 49.

    Szebeni J, Baranyi B, Savay S, Lutz LU, Jelezarova E, Bunger R, et al. The role of complement activation in hypersensitivity to pegylated liposomal doxorubicin (Doxil®). J Lipos Res 2000;10:347–61.CrossrefGoogle Scholar

  • 50.

    Zhou Z, Yang R. Rituximab treatment for chronic refractory idiopathic thrombocytopenic purpura. Cr Rev Oncol-Hem 2008;65:21–31.CrossrefGoogle Scholar

  • 51.

    Taylor RP, Lindorfer MA. Drug insight: the mechanism of action of rituximab in autoimmune disease – the immune complex decoy hypothesis. Nat Clin Pract Rheumatol 2007;3:86–95.CrossrefGoogle Scholar

  • 52.

    Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 2007;44:3823–37.CrossrefGoogle Scholar

  • 53.

    Mollnes TE, Brekke OL, Fung M, Fure H, Christiansen D, Bergseth G, et al. Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. Blood 2002;100:1869–77.Google Scholar

  • 54.

    Bexborn F, Engberg AE, Sandholm K, Mollnes TE, Hong J, Nilsson Ekdahl K. Hirudin versus heparin for use in whole blood in vitro biocompatibility models. J Biomed Mater Res A 2009;89:951–9.CrossrefGoogle Scholar

About the article

Gergely Tibor Kozma

Gergely Tibor Kozma received his MSc degree in Bioengineering at the Technical University Budapest, Faculty of Chemical Technology and Biotechnology; thereafter he obtained a PhD in Immunology and Molecular Biology at Semmelweis University. He investigated the antigen presenting processes of dendritic cells in Italy sponsored by the Marie Curie Research Training Network. During his research he mainly studied the immunological mechanisms of allergy and nano-drug induced hypersensitivity mediated by the complement system. He also has industrial experience in the field of immunology and molecular biology. He has co-authored 18 original papers with more than 400 citations.

Tamás Mészáros

Tamás Mészáros is a researcher in the Nanomedicine Research and Education Center, Semmelweis University and SeroScience Ltd., Budapest. He received his MSc degree (Immunology) from Eötvös Lóránd University in 2008, Budapest and is currently pursuing his PhD at Semmelweis University. His research interests are the complement system, nanodrugs and nanomedicine.

Tamás Schneider

Tamás Schneider is consultant at the Lymphoma Center at the National Institute of Oncology, Budapest, Hungary. He has board certifications in Internal Medicine, in Medical Oncology and Clinical Haematology. He was Committee Member of Hungarian Society of Haematology and Transfusiology (MHTT) and he is leader of the Follicular Lymphomas Working Group of the MHTT. His major scientific interest is the integration of innovative methods for the therapy of malignant lymphomas, especially diffuse large B-cell lymphomas, primary mediastinal lymphomas and follicular lymphomas. He has co-authored 39 original papers and 22 book chapters.

András Rosta

Andras Rosta is the Head of the Lymphoma Center at the National Institute of Oncology, Budapest, Hungary. He obtained his PhD degree at the Semmelweis University, Budapest. He has board certification in medicine, medical oncology and haematology. His major scientific interest is the integration of innovative methods for the therapy of malignant lymphoproliferative diseases.

Rudolf Urbanics

Rudolf Urbanics is the head of the In Vivo Laboratory of Nanomedicine Research and Education Center of Semmelweis University, and SeroScience Ltd., an immunotoxicity CRO in Budapest, Hungary. He obtained his MD diploma and his PhD degree at Semmelweis Medical University. He had teaching and research positions at the parent university (2nd Institute of Physiology) between various research positions in Germany and in the USA. He was the Deputy R&D Director and Head of CNS Pharmacology Department at Biorex R&D Co., he worked at IVAX/Drug Research Institute Budapest, as a Scientific Adviser, leading researcher in Safety and CNS Pharmacology, and later in the IVAX/Drug Research Institute, a subsidiary of TEVA, as Head of the In Vivo Pharmacology Group. He is currently working with in vivo models of nano drug-nano carrier induced, complement activation related pseudoallergic reactions (CARPA), clarifying their immuno-toxicological and safety hazards.

László Rosivall

László Rosivall MD, PhD, DSc, is a Full Professor, is the Széchenyi and Khwarizmi Prize laureate, is Head of the International Nephrology Research and Training Center, and the PhD School of Basic Medical Sciences, and is the former head of the Department of Pathophysiology, Semmelweis University Budapest, Hungary. László pioneered in recognizing and characterizing intrarenal renin-angiotensin system (RAS). Using nanotechnology he visualized the GFR in vivo and demonstrated special characteristics of the fenestration. He discovered a new, short loop feedback mechanism in the regulation of GFR. This unique JGA morphology and the high filtration volume in the afferent arteriole is one of the most striking recent observations of renal microcirculation, and questions several basic renal physiological issues.

János Szebeni

Janos Szebeni MD, PhD, DSc, MedHabil, is an Immunologist, Director of the Nanomedicine Research and Education Center at Semmelweis University, Budapest, Hungary. Janos is also founder and CEO of a contract research SME “SeroScience”, and Full Professor of (Immune) Biology at Miskolc University, Hungary. He has held various guest professor and scientific positions in Hungary and abroad, mostly in the USA where he lived for 22 years. His research on various themes in hematology, membrane biology and immunology resulted in more than 120 scientific papers (citations: >4550, H index: 35), 14 book chapters, two granted patents, a book entitled “The Complement System: Novel Roles in Health and Disease” (Kluwer, 2004). Three fields stand out where he has been most active: artificial blood, liposomes and the complement system. His original works led to the “CARPA” concept, i.e. that complement activation underlies numerous drug-induced (pseudo)allergic (anaphylactoid) reactions.

Corresponding author: Gergely Tibor Kozma, Nanomedicine Research and Education Center, Semmelweis University, 1089 Nagyvárad tér 4, Budapest, Hungary; and SeroScience Ltd, Budapest Hungary

aGergely Tibor Kozma and Tamás Mészáros: These authors contributed equally to this work.

Received: 2015-04-27

Accepted: 2015-09-05

Published Online: 2015-10-17

Published in Print: 2015-10-01

Conflict of interest statement: The authors state there is no conflict of interest. All authors have read the journal’s publication ethics and publication malpractice statement available at the journal’s website and hereby confirm that they comply with all parts applicable to the present scientific work.

Citation Information: European Journal of Nanomedicine, Volume 7, Issue 4, Pages 289–301, ISSN (Online) 1662-596X, ISSN (Print) 1662-5986, DOI: https://doi.org/10.1515/ejnm-2015-0026.

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