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Jakub Golab Department of Immunology Medical University of Warsaw

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1 Jakub Golab Department of Immunology Medical University of Warsaw
Therapeutic applications of anti-CD20 monoclonal antibodies - tumors and beyond CHMP/PDCO/CMDh Presidency meeting Jakub Golab Department of Immunology Medical University of Warsaw

2 Nobel prize in 1901 Emil Adolf von Behring Marburg University
"for his work on serum therapy…”

3

4 Antigen recognition antigen antibody

5 Nobel prize in 1984 "for the discovery of the principle for production
Georges Köhler Basel Institute for Immunology César Milstein MRC Laboratory of Molecular Biology Cambridge "for the discovery of the principle for production of monoclonal antibodies"

6 Types of monoclonal antibodies
murine Fab murine FV Fc Fab murine antibody chimeric antibody (66% of human sequence) humanised antibody (90% of human sequence) human antibody (100% of human sequence)

7

8 Monoclonal antibodies approved for clinical use in oncology
mAb name Target antigen Indication Clinical approval Rituximab CD20 Non-Hodgkin lymphoma 1997 Ibritumomab tiuxetan 2002 Tositumomab 2003 Ofatumumab Chronic lymphocytic leukemia 2009 Alemtuzumab CD52 2001 Gemtuzumab ozogamicin CD33 Acute myelogenous leukemia 2000 Bevacizumab VEGF Colorectal cancer Non-small cell lung cancer Breast cancer Glioblastoma Kidney cancer 2004 2006 2008 Panitumumab EGFR Cetuximab Head & neck cancers Nimotuzumab 2005 Trastuzumab HER2 1998 Ipilimumab CTLA-4 Malignant melanoma 2011 Brentuximab vedotin CD30 Hodgkin lymphoma Edrecolomab EpCAM 1995

9 Mechanisms of mAbs action (1):
Winiarska et al. Frontiers Biosci 2011;16:277

10 Mechanisms of mAbs action (2):
Winiarska et al. Frontiers Biosci 2011;16:277

11 Structure of CD20 antigen
Magdalena Winiarska

12 Anti-CD20 monoclonal antibodies
Antibody Clinical status Characteristics Origin Isotype Rituximab approved chimeric IgG1 Tositumomab* murine IgG2a Ofatumumab human Ibritumomab** Ocrelizumab phase 3 humanized Veltuzumab phase 2 Obinutuzumab PRO131921 AME-133 LFB-R603/EMAB-6 phase 1 * radioimmunoconjugate bound to 131iodine ** radioimmunoconjugate bound to 90ytrium

13 Development of novel anti-CD20 monoclonal antibodies:

14 Rituximab-mediated complement dependent cytotoxicity against control and statin-treated lymphoma cells Winiarska et al. PLoS Med. 2008;5(3):e64.

15 and why this finding might be important … ?
Because million people all over the world are long-term statin users The estimated number of people that should be using statins at the time being is 200 million

16 Number of cells Fluorescence intensity Winiarska et al. PLoS Med. 2008;5(3):e64.

17 PE – intracellular tail of CD20 FITC – extracellular loop of CD20
Winiarska et al. PLoS Med. 2008;5(3):e64.

18 What is the mechanism?

19 Farnesyltransferaze inhibitor (L-744,832) increases CD20 expression
CD20 promoter activity 24 h 48 h Western blotting Flow cytometry CHIP assay Surface CD20 Magda Winiarska

20 L-744,832 [μM] 1 10 100 rituximab [µg/ml] 40 80
Farnesyltransferaze inhibitor (L-744,832) potentiates rituximab-mediated CDC 1 10 100 rituximab [µg/ml] 40 80 L-744,832 [μM] Survival [% of controls] Magda Winiarska

21 Cancer patients are unlikely to give up these treatments!!!
Cancer is a disease of elderly people Increasing age is associated with: complex changes in physiology (alterations in renal and hepatic functions, decreased bone marrow reserve) Increased number of comorbid diseases (cardiovascular diseases, diabetes, rheumatic diseases, neuropsychiatric disorders) Cancer patients are unlikely to give up these treatments!!! Elderly people usually take multiple different drugs: antidiabetics statins diuretics β-blockers antidepressants anti-inflammatory drugs

22 Baker, Nature Biotech 23, 1065 (2005)

23 Potential future uses of anti-CD20 monoclonal antibodies
rheumatoid arthritis multiple sclerosis systemic lupus erythematosus autoimmune anemia autoimmune hemolytic anemia pure red cell aplasia idiopathic thrombocytopenic purpura (ITP) Wegener's granulomatosis bullous skin disorders (pemphigus, pemphigoid) type 1 diabetes mellitus Sjogren's syndrome thyroid-associated ophthalmopathy A new study from Norway suggests that rituximab (together with methotrexate) might help patients with chronic fatigue syndrome. A clinical trial is ongoing.

24 Acknowledgements Magdalena Winiarska, Jacek Bil, Dominika Nowis, Małgorzata Wańczyk, Marcin Makowski, Tomasz Świtaj, Kamil Bojarczuk, Eliza Głodkowska, Piotr Mrówka, Paweł Salwa, Tadeusz Issat, Zuzanna Kurzaj, Witold Lasek, Tomasz Stokłosa, Marek Jakóbisiak Department of Immunology Medical University of Warsaw Cezary Wójcik Department of Anatomy and Cell Biology, IUSM, USA Grzegorz M . Wilczyński Nencki Institute of Experimental Biology Wendy J.M. Mackus Patrick J. Engelberts Paul W.H.I. Parren Genmab, Utrecht, The Netherlands Łukasz Bojarski International Institute of Molecular and Cell Biology, Warsaw Maciej Siński, Ewa Wilczek, Grzegorz Basak, Zbigniew Gaciong, Elżbieta Górska, Maria Wąsik Anna Dąbrowska-Iwanicka Maria Sklodowska-Curie Memorial Cancer Center Krzysztof Warzocha Institute of Hematology, Warsaw Kazimierz Sułek Department of Clinical Hematology, Military Medical Institute Some figures were prepared using Servier Medical Art (www.servier.com)

25 T E A M Improvement of antitumor effectiveness of photodynamic therapy
In coooperation with: Patrizia Agostinis (Catholic University of Leuven, Belgium) Michael Hamblin (Wellmans Center of Photomedicine, Boston, USA) Jacek Capala (National Institutes of Health, Bethesda, USA) TEAM members: Dr. Małgorzata Firczuk Dr. Magdalena Winiarska MSc. Małgorzata Jodłowska MSc. Angelika Szokalska BSc. Justyna Chlebowska BSc. Paweł Salwa BSc. Kamil Bojarczuk BSc. Magdalena Gabrysiak TEAM coordinator: prof. Jakub Golab TEAM consultant: Dr. Dominika Nowis


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