抗体靶向治疗药物ppt课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,二级,三级,四级,五级,*,抗体靶向治疗药物,*,抗体靶向治疗药物,抗体靶向治疗药物,抗体靶向治疗药物抗体靶向治疗药物,1,邵荣光，甄永苏：,抗体靶向治疗药物,见：王晓良主编,.,应用分子药理学,.,中国协和医科大学出版社，北京，,2005,甄永苏，邵荣光主编：,抗体工程药物,化学工业出版社，北京，,2002,抗体靶向治疗药物,邵荣光，甄永苏： 抗体靶向治疗药物甄永苏，,2,抗体靶向治疗药物,抗体靶向治疗药物,3,LYMPHOCYTE,HYBRIDOMA,MYELOMA,B,淋巴细胞杂交瘤技术,抗体靶向治疗药物,LYMPHOCYTE MYELOMAB淋巴细,4,Mechanism of Action: Monoclonal Ab,Malignant,cell,Monoclonal Ab,Tumor specific Ag,Complement,Killer,leukocyte,ADCC,(Ab dependent cell-mediated cytotoxicity),CDC,(Complement dependent cytotoxicity),Monoclonal Ab,Ligand dependent apoptosis,抗体靶向治疗药物,Mechanism of Action: Monoclona,5,抗体靶向治疗药物,抗体靶向治疗药物,6,Graphic representation of progression of monoclonal antibodies from murine to chimeric to humanized to PRIMATIZED and human. The more human the antibody is, the less likely it will generate an immune response and the more utility it has for chronic (repeat) therapy.,Generations of antibody technology,抗体靶向治疗药物,Graphic representation of prog,7,抗体靶向治疗药物,抗体靶向治疗药物,8,与单抗偶联的常用,“,弹头,”,药物,毒素,植物,蓖麻毒素，相思豆毒素，,saporin,，,gelonin,，,modecin,等,微生物,绿脓杆菌外毒素，白喉毒素,药物,抗代谢类,氨基蝶呤，,MTX,，,Ara-C,，,5-FU,，,5-,氟脱氧尿苷等,蒽环类,阿霉素，柔红霉素，去甲氧柔红霉素，吗啉阿霉素等,烷基化类,苯丙氨酸氮芥，苯丁酸氮芥，丝裂霉素,C,，顺铂等,抗有丝分裂,长春花碱，秋水仙碱，鬼臼毒素等,抗生素,Calicheamicin,，博莱霉素，平阳霉素，力达霉素,核素,131,I,、,125,I,、,90,Y,、,67,Cu,、,111,In,、,99m,Tc,等,抗体靶向治疗药物,与单抗偶联的常用“弹头”药物 毒素植物,9,Physical characteristics of some therapeutic radionuclides,碘,砹,铋,镧,铜,抗体靶向治疗药物,Physical characteristics of so,10,抗体靶向治疗药物,抗体靶向治疗药物,11,抗体靶向治疗药物,抗体靶向治疗药物,12,Monoclonal antibodies in the order of FDA-approval,2006 Panitumumab (Vectibix,) EGFR Humanized IgG2,k,Colorectal cancer,2006 Ranibizumab (Lucentis,) VEGF-A Humanized IgG1,k,AMD,(,黄斑变性）,FDA: 35 SFDA: 11 15BUS,1/3 BIO,抗体靶向治疗药物,Monoclonal antibodies in the o,13,US and EU therapeutic mAb approvals to date,抗体靶向治疗药物,US and EU therapeutic mAb appr,14,1, chimeric mAbs, all products (,n,= 39);,2, oncological chimeric mAbs (,n,= 21);,3, immunological chimeric mAbs (,n,= 9);,4, chimeric mAbs, 19871997 (,n,= 20);,5, humanized mAbs, all products (,n,= 102);,6, oncological humanized mAbs (,n,= 46);,7, immunological humanized mAbs (,n,= 34);,8, humanized mAbs, 19881997 (,n,= 46).,Data are presented as two-year moving averages,Number of therapeutic mAbs entering clinical study per year,Clinical phase transition percentages for therapeutic mAbs (FDA data),抗体靶向治疗药物,1, chimeric mAbs, all products,15,Approval success rates for mAbs,Misc., miscellaneous category,including ophthalmic,neuropharmacologic and cardiovascular indications.,Therapeutic categories for mAbs in clinical study,抗体靶向治疗药物,Approval success rates for mAb,16,抗体靶向治疗药物,抗体靶向治疗药物,17,影响抗体治疗的主要障碍,1.,异源抗体的免疫原性,(Immunogenicity of xenogeneic antibodies),2.,抗原脱落进入血循环,(Shedding of antigen into circulation),3.,肿瘤内血管的失调,(Disordered vasculature in tumors),4.,肿瘤内静水压的增加,(Increased hydrostatic pressure in tumors),5.,肿瘤表面抗原的异质性,(Heterogeneity of antigen on tumor surface),6.,肿瘤效应细胞数量的限制,(Limited numbers of effector cells at tumor),7.,免疫抑制性肿瘤微环境,(Immunosuppressive tumor microenvironment),抗体靶向治疗药物,影响抗体治疗的主要障碍抗体靶向治疗药物,18,抗体靶向治疗药物,抗体靶向治疗药物,19,抗体靶向治疗药物,抗体靶向治疗药物,20,抗体靶向治疗药物,抗体靶向治疗药物,21,抗体靶向治疗药物,抗体靶向治疗药物,22,Serial microPET imaging of 124I-labeled anti-CEA scFv-Fc fragments,Parental human 1 and H310A/H435Q double mutant in LS174T xenograft-bearing mice.,The image marked scFv-Fc SM is a H310A single mutant of the mAb; scFv-Fc DM is a H310A/H435Q double mutant.,Relationship between engineered antibody format, targeting and imaging, and blood clearance,Schematic showing domain composition of engineered fragments,(25 kDa) (55 kDa) (80 kDa) (105 kDa) (150 kDa),Tumor uptake and blood clearance curves,For radioiodine-labeled anti-CEA scFv mAb fragments in athymic mice bearing subcutaneous LS174T human colon carcinoma xenografts. ID/g: injected dose per gram.,抗体靶向治疗药物,Serial microPET imaging of 124,23,Biodistribution of different mAb formats in two xenograft models,A cartoon representation of different antibody formats used for,in vivo,imaging,MicroPET scan of athymic mice with LS174T colon carcinoma (left arrow) and C6 glioma (right arrow) tumors 18 h post infusion of 124I-labeled anti-CEA T84.66 diabody, minibody or scFv-Fc,Antibody formats used in imaging,抗体靶向治疗药物,Biodistribution of different m,24,Camelid VhH-Ig and shark Ig-NARs are unusual immunoglobulin-like structures comprising a homodimeric pair of two chains of V-like and C-like domains (neither has a light chain), in which the displayed V domains bind target independently. Shark Ig-NARs comprise a homodimer of one variable domain (V-NAR) and five C-like constant domains (C-NAR). A variety of antibody fragments are depicted, including Fab, scFv, single-domain VH, VhH and V-NAR and multimeric formats, such as minibodies, bis-scFv, diabodies, triabodies, tetrabodies and chemically conjugated Fab multimers (sizes given in kilodaltons are approximate).,Schematic representation of different antibody formats, showing intact classic IgG molecules alongside camelid VhH-Ig and shark Ig-NAR immunoglobulins,抗体靶向治疗药物,Camelid VhH-Ig and shark Ig-,25,Structural comparison of antibody fragments and single domains,抗体靶向治疗药物,Structural comparison of antib,26,抗体靶向治疗药物,抗体靶向治疗药物,27,抗体靶向治疗药物,抗体靶向治疗药物,28,抗体靶向治疗药物,抗体靶向治疗药物,29,抗体靶向治疗药物,抗体靶向治疗药物,30,抗体靶向治疗药物,抗体靶向治疗药物,31,抗体靶向治疗药物,抗体靶向治疗药物,32,抗体靶向治疗药物,抗体靶向治疗药物,33,FDA,批准用于治疗肿瘤的抗体药物,Rituxan (1997):,非霍奇金,B,细胞淋巴瘤,Herceptin (1998):,乳腺癌,Mylotarg (2000):,复发的急性髓细胞性白血病,Campath-1H (2001):,难治的慢性淋巴细胞白血病,Zevalin (2002):,难治的非霍奇金,B,细胞淋巴瘤,Bexxar (2003):,难治的非霍奇金,B,细胞淋巴瘤,Erbitux (2004):,结肠直肠癌,Avastin (2004):,结肠直肠癌,Vectibix (2006):,结肠直肠癌,抗体靶向治疗药物,FDA 批准用于治疗肿瘤的抗体药物Rituxan (1997,34,抗体靶向治疗药物,抗体靶向治疗药物,35,抗体靶向治疗药物,抗体靶向治疗药物,36,抗体靶向治疗药物,抗体靶向治疗药物,37,抗体靶向治疗药物,抗体靶向治疗药物,38,抗体靶向治疗药物,抗体靶向治疗药物,39,抗体靶向治疗药物,抗体靶向治疗药物,40,单克隆抗体肿瘤靶向治疗,bind to antigens present preferentially or exclusively on tumor cells.,Zevalin,Bexxar,Mylotarg,抗体靶向治疗药物,单克隆抗体肿瘤靶向治疗 ZevalinMylotarg抗体靶,41,单克隆抗体作为肿瘤治疗的体内应用策略,Antibody Alone,Complement mediated cytotoxicity (CMC),Antibody dependent cell-mediated cytotoxicity (ADCC),Regulatory (ligand/receptor) interactions,Anti-idiotype vaccine,Immunoconjugates,Radiolabeled Antibodies,Immunotoxins,Chemotherapy-Antibody Conjugates,Cytokine Immunoconjugates,Cellular Immunoconjugates,抗体靶向治疗药物,单克隆抗体作为肿瘤治疗的体内应用策略Antibody Alo,42,Antibody fragments in clinical and preclinical development,抗体靶向治疗药物,Antibody fragments in clinical,43,Antibody fragments in clinical and preclinical development,抗体靶向治疗药物,Antibody fragments in clinical,44,Therapeutic mAbs currently in phase 3 studies,CTLA, cytotoxic T-lymphocyte associated protein; EGF, epidermal growth factor; MRSA, methicillin-resistant,Staphylococcus aureus,; RANKL, receptor for activation of nuclear factor-B ligand; RSV, respiratory syncytial virus; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.,抗体靶向治疗药物,Therapeutic mAbs currently in,45,近几年处在临床实验中的免疫毒素,AAPS J 2006,抗体靶向治疗药物,近几年处在临床实验中的免疫毒素AAPS J 2006抗体靶向,46,近几年处在临床实验中的免疫毒素,AAPS J 2006,抗体靶向治疗药物,近几年处在临床实验中的免疫毒素AAPS J 2006抗体靶向,47,抗体靶向治疗药物,抗体靶向治疗药物,48,Thanks You!,抗体靶向治疗药物,Thanks You!抗体靶向治疗药物,49,Schematic representation of immunoglobulin fragments,Fab,scFv,diabody,dAb (VH or VL),Possible different configurations of fusion proteins of cytokines with either full-length antibody molecules or the antigen-binding sites (scFv) are depicted. The cytokine or chemokine moiety has been fused at the N- or C-terminal of the heavy chain (a) and (b), or at the N-terminal end (c) or C-terminal end of the scFv (d) or both (e). In addition, fusion proteins of two cytokines have also been described.,Immunocytokines and their configurations,抗体靶向治疗药物,Schematic representation of im,50,