Microsoft PowerPoint - 15 Application of mAbs.pptx

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1 Pharmaceutical Biotechnology Application of mabs By Yuqiong Xia 2014

2 Keywords oncologic diseases, cancer, tumor, recurrence, Epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGF) receptor, CD (cluster of differentiation) Immunosuppression, TNF, inflammatory, integrin 2

3 Outline mabs in Cancer Therapy mabs in Solid Organ Transplantation mabs in Anti-inflammatory Therapy 3

4 Cancer cells img jpg

5 Therapeutic mabs in cancer Improve overall survival Increase the time to progression Delay the time to recurrence of many oncologic diseases 5

6 The target of therapeutic mabs CD cell Epidermal growth factor receptor (EGFR) Vascular endothelial growth factor (VEGF) receptor 6

7 CD (cluster of differentiation) 分化抗原 Cell surface molecules providing targets 7

8 FDA-approved mabs in cancer 生物制药工程夏玉琼西安电子科技大学 8

9 Alemtuzumab Target kda cell surface glycoprotein CD52 CD52+ on lymphocytes, monocytes, NK cells, macrophages and eosinophils CD52- on RBC, platelet or stem cells CD52 are highly expressed in chronic lymphocytic leukemia( 慢性淋巴细胞白血病 ), non-hodgkin lymphoma( 非霍奇金淋巴瘤 ), acute lymphoblastic leukemia ( 成淋巴细胞性白血病 ) CD52 is not shed, a good therapeutic target 9

10 Alemtuzumab triggers CDCC 生物制药工程夏玉琼西安电子科技大学 10

11 Alemtuzumab triggers ADCC 生物制药工程夏玉琼西安电子科技大学 11

12 Trastuzumab (Herceptin ) A recombinant DNA derived humanized MAb (IgG1 kappa) that targets the extracellular domain of the human EGFR 2 receptor. This receptor-antibody interaction, through a series of other cellular actions, induces autophosphorylation of the tyrosine kinase internal domain resulting in decreased tumorigenic potential and possibly reversal of chemoresistance 12

13 EGFR in cancer EGFR or HER-1 and EGFR 2 or HER-2 are transmembrane glycoproteins constitutively expressed in many normal epithelial tissues including skin and hair follicle ( 毛囊 ) and are overexpressed in many cancers including the colon( 结肠 ), rectum( 直肠 ) and breast 13

14 EGFR 2 or HER-2 in cancer 生物制药工程夏玉琼西安电子科技大学 14

15 Trastuzumab (Herceptin ) slows cancer growing 15

16 Bevacizumab (Avastin ) Currently the only FDA approved VEGF inhibitor Consist of a normal human IgG1 (93%) and the VEGF binding residues from a murine neutralizing antibody (7%) Produced in a system containing Chinese hamster ovary mammalian cell expression and a gentamicin( 庆大霉素 )-containing nutrient medium 16

17 VEGF in cancer Tumor reaches mm, it can no longer supply itself with nutrients and oxygen from nearby small blood vessels Tumor secretes proteins called vascular endothelial growth factor (VEGF) VEGF attach to nearby blood vessels and stimulate growth 17

18 VEGF in cancer VEGF can induce neovascularization ( 新血管形成 ) for malignant cells in an autocrine fashion High levels of VEGF are correlated with poor prognosis( 预后 ), disease recurrence, and metastases( 转移 ) in many tumors. 18

19 Bevacizumab can inhibit VEGF in cancer 19 Bevacizumab blocks the signals from the tumor that prompt blood vessel growth. Without nutrients and oxygen, the tumor stops growing.

20 Outline mabs in Cancer Therapy mabs in Solid Organ Transplantation mabs in Anti-inflammatory Therapy 20

21 mabs in solid organ transplantation Inhibit immune response Decrease the immunoreactivity of potential transplant recipient before transplantation Induce global immunosuppression at the time of transplantation Reduce exposure to maintenance immunosuppressive agents Treat acute allograft rejection 21

22 mabs in Solid Organ Transplantation 22

23 Alemtuzumab (Campath-1H ) Target CD52 on the surface of peripheral blood lymphocytes, NK cells, monocytes, macrophages, thymocytes ( 胸腺细胞 ) Also treat cancer 23

24 Daclizumab 生物制药工程夏玉琼西安电子科技大学 Target CD25α on the surface of IL-2 dependent T cell 24 Original T cell Daclizumab reduces IL-2 signaling Daclizumab expands CD56 IL-10 producing negative NK cell

25 Muromonab-OKT3 Target CD3 on T cell surface 25

26 Rituximab (Rituxan ) Target CD20 on B cell surface Also treat cancer 26

27 Outline mabs in Cancer Therapy mabs in Solid Organ Transplantation mabs in Anti-inflammatory Therapy 27

28 Inflammatory diseases Arthritis ( 关节炎 ) Psoriasis ( 牛皮癣 ) Multiple sclerosis ( 多发性硬化 ) Allergic asthma ( 过敏性哮喘 ) 28

29 Arthritis and TNF-α RA (rheumatoid arthritis 风湿性关节炎 ) TNF-α is now recognized as a central inflammatory cytokine in RA 29

30 Three FDA-approved mabs for RA Infliximab, chimeric mab Adalimumab, humanized mab Etanercept receptor-fc fusion protein 30

Infliximab Neutralize biological activity of both soluble and transmembrane forms of TNF-α 31 http://infliximab.

31 Infliximab Neutralize biological activity of both soluble and transmembrane forms of TNF-α 31 ism_of_action.jpg

Etanercept 32 http://www.hindawi.com/journals/ecam/2013/168134.fig.001.

32 Etanercept

33 Psoriasis ( 牛皮癣 ) 33

34 Three FDA-approved mabs for Psoriasis ( 牛皮癣 ) Efalizumab (Raptiva ) Target CD11a subunit of leukocyte function antigen-1 (LFA-1) on leukocytes Etanercept (Enbrel ) Target TNFα Mentioned in treating RA Alefacept (Amevive ) Binds T and NK cells via CD2 34

35 Three FDA-approved mabs for Psoriasis ( 牛皮癣 ) 35

耳鸣 http://www.nursestip.co m/files/multiple%20scler osis.

36 耳鸣 m/files/multiple%20scler osis.jpg 尿滞留痉挛性膀胱便秘复视视力模糊眼球震颤吞咽困难发音困难肌肉痉挛运动失调眩晕 36 The presence of immune cells in the brain is a prominent feature of MS

37 How do immune cells enter brain α4 integrin on lymphocyte binds to vascular cell adhesion molecule 1 (VCAM1) on inflamed brain endothelium. 37

38 Integrin Integrins are transmembrane receptors that are the bridges for cell-cell and cell-extracellular matrix (ECM) interactions 38

How does natalizumab work 39 http://jcb.

39 How does natalizumab work 39

40 Allergic asthma 40

How does allergic asthma occur 41 http://openi.nlm.

41 How does allergic asthma occur 41

42 Omalizumab Binds to CR3 region of IgE to prevent its interaction with FcR1 and FcR2 on effector cells 42

43 Summary mabs in cancer Target CD, VEGFR or EGFR mabs in solid organ transplantation Target CD mabs in anti-inflammatory therapy Target TNFα in RA; target CD and TNFα in psoriasis; target α4 integrin in MS; target IgE in allergic asthma 43

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