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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


CiteScore 2017: 0.78

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1662-596X
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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

Abstract

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

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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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