美罗华在淋巴瘤治疗中的应用.ppt
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1、Lymphoma: A Decade of Rituximab and the Next Chapter,Wenru Song, MD, PhD Pfizer Global Research & Development-Oncology & Baylor Institute for Immunology Research,Outline,Historical perspective & reflections in Rituximabs development Impact of Rituximab -Lymphoma -Rheumatoid arthristis, lupus, and ot
2、her autoimmune diseases -Other solid tumors New emerging therapies in lymphoma,Monoclonal Antibodies from Hybridoma Technology,Georges Kohler and Cesar Milstein (1975) in Nature. Monoclonal antibodies are artificially produced against a specific antigen. Production of monoclonal antibodies (mAbs) wi
3、th hybridoma technique. With this technique a group of lymphocytes producing all the same antibody protein is obtained. revolutionizing diagnostic medicine. Mabs against cancer, infections, and other diseases.,History of Monoclonal Antibody (Mab) Therapy,Murine Mab *Ibritomomab *tositumomab,Humanize
4、d *trastuzumab *bevacizumab *TheraCIM,Chimeric *Cetuximab *rituximab *131I -Ch-TNT,Human *panitumumab,1975: First murine Mab from hybridoma (Kohler and Milstein, Nature) 1980s-90s: Humanization of murine Mabs (chimeric Mab) 1997: 1st Mab for cancer immunotherapy: Rituximab 1998: Fully human Mab: -Xe
5、noMouse (Abgenix), HuMab-mouse (Medarex) or Phage scFv library,1997- 2007: 11 Mabs approved for use in cancer by US FDA,FDA Approved Monoclonal Antibodies,The “Ups & Downs” of Monoclonal Antibody (mAb) Development,“Hey, these are magic bullets”,“mAbs should be even in soup”,“I heard there are some p
6、roblems”,“Id apply them only to my enemies”,“mAbs work in some cases!”,1975,1982,1986,1994,1997,First mAb produced,Success in lymphoma,OKT3 approved,Lilly purchase Hybritech ($350m),Wellcome drops Campath,Panorex & ReoPro app.,Rituximab,Genetic engineering,Jesus Gomez-Navarro,5th most common cancer
7、in both men and women in US Hodgkins lymphoma and Non-Hodgkins Lymphoma (NHL) Incidence increases 3-4% annually (doubled in last 2 decades), one of only two cancers with continued increase Many sub-types of NHL, majority with B-cell origin -Diffuse large B cell lymphoma (DLBCL): most common NHL (30%
8、) -Follicular lymphoma (FL): 2nd most common NHL (20%) -Mantle cell lymphoma (MCL): poorest prognosis (6-10%) Leading the oncology field in disease biology, diagnosis, and therapy (radiation, chemo, immunotherapy, chemo-immunotherapy),Lymphoma,Rituximab (Rituxan, MabThera) Targeted therapy -CD20 on
9、lymphoma -direct tumor killing by Rituximab Immunotherapy -host immune system -indirect tumor killing by host immune cells,Natural Killler Cells Monocytes,FcR,2) Complement-mediated Killing,1) Apoptosis, Anti-proliferation,3) Antibody-dependent Cellular Cytotoxicity (ADCC),Tumor Cell,FcR,Dendritic C
10、ells,4) Antigen Presentation and Cross-priming,Rituximab Anti-tumor Effect: Proposed Mechanisms,CD20 or other tumor Ags,T Cells,Vaccine-like effect after Rituximab Treatment,* In vivo: longer duration of remission after re-treatment with Rituxan than the initial Rituxan treatment *In vitro: enhanced
11、 cross-priming of cytoxic T cells by Rituxan-induced apopotic tumor cells,FcR,Dendritic Cells,T Cells,Tumor,1st FDA-approved therapeutic antibody to treat cancer (11/1997) 1st fully integrated into chemo-immunotherapy (R-chemo) 1st and only biologic therapy in combination with chemo (R-CVP, etc) tha
12、t improved progress-free survival (PFS) in pts with 1st line follicular lymphoma, with emerging trend to improve overall survival for the 1st time 1st treatment of any kind (with CHOP or anthracycline-based chemo) to have improved overall survival (OS) in 1st line DLBCL in more than 25 yrs,Rituximab
13、 (Rituxan, MabThera): A history of firsts,Chimeric mab to CD20, IgG1 Weekly x 4 (375mg/m2): Rapid CD20+B cell depletion in blood (100%-few days), BM (90%-1wk), and LN (80%- a few wks), return normal level in 9-12 months Onset and maximal clinical response: 1mt and 3-4 mts Initial Rx in relapsed FL:
14、50% ORR (6%CR; 44%PR); mDR 11mt; Re-Rx: ORR 40% (10%CR/30%PR); mDR 15mt Maintenance Rx: Qwk X4 every 6 mt or Q3mt for 2 yrs No change of serum Ig and incidence of infection, and the T cell response from vaccination is still OK,Rituximab (Rituxan, MabThera): Facts,Anti-idiotype (Id) antibody,Lymphoma
15、 B cell,Two lines of Monoclonal Antibody Therapy Development For Lymphoma,Rituximab,CD20,Tumor Idiotype (Id),New England Journal of Medicine, 306:517. 1982 Treatment of B Cell Lymphoma with Monoclonal Anti-Idiotype Antibody Richard A Miller, David G. Maloney, Roger Warnke, and Ronald Levy,Cancer Res
16、. 1980;40:3147 Serotherapy of a patient with a monoclonal antibody (murine anti-human CD20 Mab) directed against a human lymphoma-associated antigen Lee Nadler, et al,Antibodies: a slow breakthrough of a new technology,Technologies to reduce immunogenicity of monoclonal antibodies: technological evo
17、lution towards humanization, human antibodies innovation biography of drugs,Christian Zeller,1976 1978, 1985, 1986 12/1992 03/1993 1995 03/96 11/97, 06/98 2006,IND from IDEC,1st pt In P1 Levy,last pt In P3,FDA,EMEA,1st line; R-chemo; maintenance,Timeline of Rituximab Development,IDEC & Genentech/Roc
18、he Co-develop,Hybritech,IDEC,Biotherapy System Levy/Miller,Genentech Boyer/Cohen,CD20 gene In 1980 Nadler,IDEC,Development of IDECs Stock Prices,Christian Zeller,Phase I trial done IDEC & Genentech Co-develop,FDA approval,Phase I: 1993-94 -single dose: 10, 50, 100, 250, 500 mg/m2, No MTD -15 pts: 2
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