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1、Lymphoma: A Decade of Rituximab and the Next ChapterWenru Song, MD, PhDPfizer Global Research 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 sti
2、ll OKRituximab (Rituxan, MabThera): FactsAnti-idiotype (Id) antibodyLymphoma B cellTwo lines of Monoclonal Antibody Therapy Development For LymphomaRituximab CD20Tumor Idiotype (Id)14New England Journal of Medicine, 306:517. 1982Treatment of B Cell Lymphoma with Monoclonal Anti-Idiotype AntibodyRich
3、ard A Miller, David G. Maloney, Roger Warnke, and Ronald LevyCancer Res. 1980;40:3147Serotherapy of a patient with a monoclonal antibody (murine anti-human CD20 Mab) directed against a human lymphoma-associated antigenLee Nadler, et al Antibodies: a slow breakthrough of a new technology2006 Panitumu
4、mab (Vectibix)19751984198619901994Technologies to reduce immunogenicity of monoclonal antibodies: technological evolution towards humanization, human antibodies innovation biography of drugsChristian Zeller1976 1978, 1985, 1986 12/1992 03/1993 1995 03/96 11/97, 06/98 2006 IND from IDEC1st pt In P1 L
5、evylast ptIn P3FDA EMEA1st line; R-chemo; maintenanceTimeline of Rituximab DevelopmentIDEC 359:613Randomized Trials of Maintenance Treatment with Rituximab versus ObservationRandomized Trials of Maintenance Treatment with Rituximab versus ObservationCheson B, Leonard J. N Engl J Med 2008;359:613-626
6、Extended Uses of Rituximab: Integration into Lymphoma Standard of Care Salvage therapy for chemo-refractory or relapsed: low grade Up-front therapy Delay or avoid chemotherapylow grade Combination therapy With chemotherapy With other biologicals- enhance ADCC With other monoclonals Maintenance thera
7、py Mortality Rates of Non-Hodgkins Lymphoma25Rituximab PublicationsNumber of publicationsYearPublications1st clinical trial160180200200801001201400204060Jan/91929394959697989900FDA approvalPivotal trial results-1 million pts worldwide being treated4378 in 2008Rituxan / MabThera: a blockbusterChristi
8、an ZellerTop 5 Best Selling Oncology Drugs in 2007RankOncology ProductCompany2007 WW Revenue ($M)Oncology Indications1RituxanGenentech/Biogen- IDEC$3,820NHL2HerceptinGenentech$3,356BC3AvastinGenentech$2,880NSCLC, CRC, BC4GleevecNovartis$2,737CML, GIST, ALL5EloxatinSanofi Aventis$2,456CRCPfizer-Oncol
9、ogyApproved MAbs for Cancer TherapyTargetNameTumorYear FormatHer-2Trastuzumab (Herceptin)Breast1998Humanized IgG1VEGFBevacizumab (Avastin)Colon, NSCLC, Breast2004Humanized IgG1EGFRCetuximab (Erbitux)Colon, H/N2004chimeric IgG1Panitumumab (Vectibix)Colon 2006Fully human IgG2Nimotuzumab* (Thera CMI)Na
10、sopharyngel2005 Humanized IgG1DAN- associated131I -Ch-TNT*Lung2003Chemiric, 131ICD20RituximabNHL1997Chimeric IgG1CD52Alemtuzumab (Campath-1H)CLL2001Humanized IgG1CD33Gemtuzumab (Myelotarg)AML 2000Humanized IgM- calichamycinCD20Ibritumomab (Zevalin)NHL2002Murine 90Y-IgG1CD20Tositumomab (Bexxar)NHL200
11、3Murine131I-IgG1*First approved in ChinaOutline Historical perspective in Rituximabs development Impact of Rituximab -Lymphoma -Rheumatoid arthristis, lupus, and other autoimmune diseases -Other solid tumors New emerging therapies in lymphoma (phase I-III trials) -human or humanized anti-CD20: enhan
12、ced ADCC, CDC -Other new targets: CD22, CD40, CD80, mTOR, HDAC, Revlimid, Avastin, Velcade, PKC-b, TRAIL, Bcl-2, CTLA-4 -Rituxan-based combinational Bio-Rx -In situ vaccines (dendritic cells, CpG)Cheson B, Leonard J. N Engl J Med 2008;359:613-626Unconjugated Monoclonal Antibodies for B-Cell CancersD
13、rug/Sponsor DesignPhase Line of TherapyGaliximab (CD80) (Biogen)Galiximab +Rituxan (R) vs Rituxan (R)IIIRelapsed or refractory FLVelcade (Millennium/JJ)Velcade + Rituxan vs Rituxan IIIRelpased or refractory FLSGN-40 (CD40) (SG/Genentech)SGN-40 (CD40)+ RituxanI Relapsed FL and maginal zone NHLSGN-40
14、(SG/Genentech)SGN-40+ R-chemovs R-chemoIIRelapsed DLBCLRevlimid (Celgene)Revlimid + RituxanIIRelapsed or refractory FLOfatumumab (2nd generation Rituxan GSK/GeneMab)Ofatumumab vs RituxanIIIRelapsed or refractory FLEpratuzumab (CD22) (Immunomedics/CALGB)Epratuzumab + RituxanII1st line FLInvestigation
15、al Combination BioRx for B-Cell Cancers Most potent “antigen-presenting cells” Reside in tissues to collect antigen - travel to lymph nodes Co-culture with antigens - cellular vaccineDendritic CellsIn situ Vaccination with DCChemo+DC 15/15DCChemo+Chemo 0/8DC 0/7No Rx 0/9Mean Tumor SizeDays post tumo
16、r implantationSong Stanford) -Locally advanced pancreatic cancer (phase I/II; Stanford)-Lymphoma and other solid tumors (phase I/II; Baylor)Intratumoral DC Vaccination + Conventional Therapy: From Lab to ClinicCpG bridges innate and adaptive immunity Bacterial DNA ACGTTGAGTTCGTACGCATACGA Vertebrate DNA AGCTTGAGTCmCGGATGGGTAAGA Immune system recognizes CpG through TLR-9 and induces activation of
