《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：甄永苏，邵荣光主编： 抗体工程药物 化学工业出版社，北京，2002.LYMPHOCYTE HYBRIDOMA MYELOMAB B淋巴细胞杂交瘤技术淋巴细胞杂交瘤技术.Mechanism of Action: Monoclonal AbMalignantcellMonoclonal AbTumor specific AgComplementKillerleukocyteADCC(Ab dependent cell-mediated cytotoxi

2、city)CDC(Complement dependent cytotoxicity)Monoclonal AbLigand 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

3、more utility it has for chronic (repeat) therapy.Generations of antibody technology. 毒素毒素植物植物 蓖麻毒素，相思豆毒素，蓖麻毒素，相思豆毒素，saporinsaporin，geloningelonin，modecinmodecin等等微生物微生物 绿脓杆菌外毒素，白喉毒素绿脓杆菌外毒素，白喉毒素 药物药物抗代谢类抗代谢类 氨基蝶呤，氨基蝶呤，MTXMTX，Ara-CAra-C，5-FU5-FU，5- 5-氟脱氧尿苷等氟脱氧尿苷等蒽环类蒽环类 阿霉素，柔红霉素，去甲氧柔红霉素，吗啉阿霉素等阿霉素，柔红霉素，

4、去甲氧柔红霉素，吗啉阿霉素等烷基化类烷基化类 苯丙氨酸氮芥，苯丁酸氮芥，丝裂霉素苯丙氨酸氮芥，苯丁酸氮芥，丝裂霉素C C，顺铂等，顺铂等抗有丝分裂抗有丝分裂 长春花碱，秋水仙碱，鬼臼毒素等长春花碱，秋水仙碱，鬼臼毒素等抗生素抗生素 CalicheamicinCalicheamicin，博莱霉素，平阳霉素，力达霉素，博莱霉素，平阳霉素，力达霉素 核素核素 131131I I、125I、9090Y Y 、6767CuCu 、111111In In 、99mTc等等.Physical characteristics of some therapeutic radionuclides碘碘砹砹铋铋镧镧铜

5、铜.Monoclonal antibodies in the order of FDA-approval2006 Panitumumab (Vectibix) EGFR Humanized IgG2k k Colorectal cancer2006 Ranibizumab (Lucentis) VEGF-A Humanized IgG1k k AMD (黄斑变性）FDA: 35 SFDA: 11 15BUSFDA: 35 SFDA: 11 15BUS 1/3 BIO1/3 BIO.US and EU therapeutic mAb approvals to date.1, chimeric m

6、Abs, 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

7、= 46). Data are presented as two-year moving averagesNumber of therapeutic mAbs entering clinical study per yearClinical phase transition percentages for therapeutic mAbs (FDA data).Approval success rates for mAbsMisc., miscellaneous categoryincluding ophthalmic, neuropharmacologic and cardiovascula

8、r indications.Therapeutic categories for mAbs in clinical study.影响抗体治疗的主要障碍影响抗体治疗的主要障碍1. 1. 异源抗体的免疫原性异源抗体的免疫原性 (Immunogenicity of xenogeneic antibodies)(Immunogenicity of xenogeneic antibodies)2. 2. 抗原脱落进入血循环抗原脱落进入血循环 (Shedding of antigen into circulation)(Shedding of antigen into circulation)3. 3.

9、肿瘤内血管的失调肿瘤内血管的失调 (Disordered vasculature in tumors)(Disordered vasculature in tumors)4. 4. 肿瘤内静水压的增加肿瘤内静水压的增加 (Increased hydrostatic pressure in tumors)(Increased hydrostatic pressure in tumors)5. 5. 肿瘤表面抗原的异质性肿瘤表面抗原的异质性 (Heterogeneity of antigen on tumor surface)(Heterogeneity of antigen on tumor s

10、urface)6. 6. 肿瘤效应细胞数量的限制肿瘤效应细胞数量的限制 (Limited numbers of effector cells at tumor)(Limited numbers of effector cells at tumor)7. 7. 免疫抑制性肿瘤微环境免疫抑制性肿瘤微环境 (Immunosuppressive tumor microenvironment)(Immunosuppressive tumor microenvironment).Serial microPET imaging of 124I-labeled anti-CEA scFv-Fc fragmen

11、ts 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 clearanceSchematic showing

12、 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. .Biodistrib

13、ution of different mAb formats in two xenograft modelsA 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,

14、minibody or scFv-FcAntibody 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-

15、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 chemicall

16、y 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.单克隆抗体肿瘤靶向治疗单克隆

17、抗体肿瘤靶向治疗 bind to antigens present preferentially or exclusively on tumor cells.ZevalinZevalinBexxarBexxarMylotargMylotarg.单克隆抗体作为肿瘤治疗的体内应用策略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) intera

18、ctions Anti-idiotype vaccineImmunoconjugates 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 mAb

19、s currently in phase 3 studiesCTLA, 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 endothel