1、Lymphoma: A Decade of Rituximab and the Next ChapterWenru Song, MD, PhDPfizer Global Research & Development-Oncology&Baylor Institute for Immunology ResearchOutline Historical perspective & reflections in Rituximabs development Impact of Rituximab-Lymphoma-Rheumatoid arthristis, lupus, and other aut
2、oimmune diseases-Other solid tumors New emerging therapies in lymphomaMonoclonal Antibodies from Hybridoma TechnologyAntigenCells Fuse into a HybridomaCancerousPlasma CellAntibody-producingPlasma CellMonoclonal Antibodies Georges Kohler and Cesar Milstein (1975) in Nature. Monoclonal antibodies are
3、artificially produced against a specific antigen. Production of monoclonal antibodies (mAbs) with 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 disea
4、ses.History of Monoclonal Antibody (Mab) TherapyMurine Mab*Ibritomomab*tositumomabHumanized*trastuzumab*bevacizumab*TheraCIMChimeric*Cetuximab*rituximab *131I -Ch-TNTHuman*panitumumab CH1CH3CH2VHCLVL CDR1975: First murine Mab from hybridoma (Kohler and Milstein, Nature)1980s-90s: Humanization of mur
5、ine Mabs (chimeric Mab) 2019: 1st Mab for cancer immunotherapy: Rituximab2019: Fully human Mab: -XenoMouse (Abgenix), HuMab-mouse (Medarex) or Phage scFv library2019- 2019: 11 Mabs approved for use in cancer by US FDAFDA Approved Monoclonal AntibodiesYEAR Product Target Indication1986 Orthoclone CD3
6、 Transplant Rejection1994 ReoPro GPIIa/IIIb Angioplasty2019 Rituxan CD20 B Cell Lymphoma2019 Zenapax IL2R Transplant Rejection2019 Simulect IL2R Transplant Rejection2019 Remicade TNF Crohns, RA2019 Herceptin Her2 Breast Cancer2000 Mylotarg CD33 AML2019 Campath CD52 CLL2019 Zevalin CD20 B Cell Lympho
7、ma2019 Bexxar CD20 B Cell Lymphoma2019 Raptiva CD11a Psoriasis2019 Avastin VEGF Colon Cancer20192019201920192019ErbituxTysabriLucentisVectibixSolirisEGFRa4b1 integrinVEGF-AEGFRC5Colon CancerMultiple sclerosisMacular degenerationColon CancerPNHThe “Ups & Downs” of Monoclonal Antibody (mAb) Developmen
8、t “Hey, these are magic bullets”“mAbs should be even in soup”“I heard there are some problems”“Id apply them only to my enemies”“mAbs work in some cases!”1975 1982 1986 1994 2019First mAb producedSuccess in lymphomaOKT3 approvedLilly purchase Hybritech ($350m)Wellcome drops CampathPanorex &ReoPro ap
9、p. RituximabGenetic engineeringJesus Gomez-Navarro 5th most common cancer 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
10、B-cell origin-Diffuse large B cell lymphoma (DLBCL): most common NHL (30%) -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-immunoth
11、erapy) LymphomaRituximab (Rituxan, MabThera) Targeted therapy -CD20 on lymphoma -direct tumor killing by RituximabImmunotherapy-host immune system-indirect tumor killing by host immune cellsNatural Killler CellsMonocytesFcR2) Complement-mediated Killing1) Apoptosis, Anti-proliferation3) Antibody-dep
12、endent CellularCytotoxicity (ADCC)Tumor CellFcRDendritic Cells4) Antigen Presentationand Cross-primingRituximab Anti-tumor Effect: Proposed MechanismsCD20 or other tumor AgsT CellsVaccine-like effect after Rituximab Treatment* In vivo: longer duration of remission after re-treatment with Rituxan than the initial Rituxan treatment *In vitro: enhanced cross-priming of cytoxic T cells by Rituxan-induced apopotic tumor cellsFcRDendritic CellsT CellsTumor
