课件：抗体靶向治疗药物.ppt

抗体靶向治疗药物 邵荣光 医药生物技术研究所,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,B淋巴细胞杂交瘤技术,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,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,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 131I、125I、90Y 、67Cu 、111In 、99mTc等,Physical characteristics of some therapeutic radionuclides,碘 砹 铋 镧 铜,Monoclonal antibodies in the order of FDA-approval,FDA: 35 SFDA: 11 15BUS 1/3 BIO,US and EU therapeutic mAb approvals to date,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),Approval success rates for mAbs,Misc., miscellaneous category including ophthalmic, neuropharmacologic and cardiovascular indications.,Therapeutic categories for mAbs in clinical study,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),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.,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,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,Structural comparison of antibody fragments and single domains,2019/9/1,27,可编辑,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,单克隆抗体肿瘤靶向治疗 bind to antigens present preferentially or exclusively on tumor cells.,Zevalin Bexxar,Mylotarg,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,Antibody fragments in clinical and preclinical development,Antibody fragments in clinical and preclinical development,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.,近几年处在临床实验中的免疫毒素,AAPS J 2006,近几年处在临床实验中的免疫毒素,AAPS J 2006,Thanks You!,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 c