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

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Presentation on theme: "Therapeutic applications of anti- CD20 monoclonal antibodies - tumors and beyond Jakub Golab Department of Immunology Medical University of Warsaw CHMP/PDCO/CMDh."— Presentation transcript:

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

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

3

4 antigenantibody Antigen recognition

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

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

7

8 mAb nameTarget antigenIndicationClinical approval RituximabCD20Non-Hodgkin lymphoma1997 Ibritumomab tiuxetanCD20Non-Hodgkin lymphoma2002 TositumomabCD20Non-Hodgkin lymphoma2003 OfatumumabCD20Chronic lymphocytic leukemia2009 AlemtuzumabCD52Chronic lymphocytic leukemia2001 Gemtuzumab ozogamicinCD33Acute myelogenous leukemia2000 BevacizumabVEGFColorectal cancer Non-small cell lung cancer Breast cancer Glioblastoma Kidney cancer PanitumumabEGFRColorectal cancer2006 CetuximabEGFRColorectal cancer Head & neck cancers NimotuzumabEGFRHead & neck cancers2005 TrastuzumabHER2Breast cancer1998 IpilimumabCTLA-4Malignant melanoma2011 Brentuximab vedotinCD30Hodgkin lymphoma2011 EdrecolomabEpCAMColorectal cancer1995 Monoclonal antibodies approved for clinical use in oncology

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 Antibody Clinical status Characteristics OriginIsotype RituximabapprovedchimericIgG1 Tositumomab*approvedmurineIgG2a OfatumumabapprovedhumanIgG1 Ibritumomab**approvedmurineIgG1 Ocrelizumabphase 3humanizedIgG1 Veltuzumabphase 2humanizedIgG1 Obinutuzumabphase 2humanizedIgG1 PRO131921phase 2humanizedIgG1 AME-133phase 2humanizedIgG1 LFB-R603/EMAB-6phase 1chimericIgG1 * radioimmunoconjugate bound to 131 iodine ** radioimmunoconjugate bound to 90 ytrium Anti-CD20 monoclonal antibodies

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

20 Survival [% of controls] L-744,832 [μM] Magda Winiarska Farnesyltransferaze inhibitor (L-744,832) potentiates rituximab-mediated CDC

21 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) Elderly people usually take multiple different drugs: antidiabetics statins diuretics β-blockers antidepressants anti-inflammatory drugs Cancer patients are unlikely to give up these treatments!!!

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 Some figures were prepared using Servier Medical Art (www.servier.com) 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 WójcikDepartment of Anatomy and Cell Biology, IUSM, USA Grzegorz M. WilczyńskiNencki Institute of Experimental Biology Wendy J.M. Mackus Patrick J. Engelberts Paul W.H.I. Parren Genmab, Utrecht, The Netherlands Łukasz BojarskiInternational Institute of Molecular and Cell Biology, Warsaw Maciej Siński, Ewa Wilczek, Grzegorz Basak, Zbigniew Gaciong, Elżbieta Górska, Maria Wąsik Medical University of Warsaw Anna Dąbrowska-IwanickaMaria Sklodowska-Curie Memorial Cancer Center Krzysztof WarzochaInstitute of Hematology, Warsaw Kazimierz SułekDepartment of Clinical Hematology, Military Medical Institute

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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