Microsoft PowerPoint - 14 Monoclonal Antibodies.pptx

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1 Pharmaceutical Biotechnology Monoclonal Antibodies By Yuqiong Xia 2014

2 Keywords Monoclonal antibody (mab), epitope, myeloma Chimeric, complement, complementary Phage display, hinge, cytotoxity Apoptosis, preclinical 2

3 Outline Introduction to mabs Structure of mabs Therapeutic mechanism of mabs Preclinical and clinical assessments 3

4 What is monoclonal antibody Monospecific antibodies made by identical immune cells Have monovalent affinity, in that they bind to the same epitope 4

5 How to produce mab 5

6 Who invent the production method of mab Milstein and Kohler, hybridoma technology 1975 present the technology 1984 Noble Prize 1986 market authorization 6

7 Detailed production of mabs 生物制药工程夏玉琼西安电子科技大学 7

8 The application of mabs Oncology 9 mabs, 2 immunoconjugates Transplantation 3 mabs Inflammatory diseases 6 mabs, 3 Fc-fusion proteins Cardiovascular area 1 mabs 8

9 The advantage of mabs Safe Avoid unnecessary exposure to non-target organs Safer than chemotherapeutic treatment Molecular targeted medicine 9

10 Outline Introduction to mabs Structure of mabs Therapeutic mechanism of mabs Preclinical and clinical assessments 10

11 Structure of IgG Y-shaped 2 H chains 2 L chains S-S bond V H and V L C H and C L 11

12 Structure of IgG 2 heavy chains (2 H-chains) Variable regions: V H Constant regions: C H, effector recognition and binding 2 light chains (2 L-chains) Variable regions: V L Constant regions: C L, effector recognition and binding 12

13 Different humanized mabs 13 0% 60%-70% 90%-95% 100% Decreased immunogenic risks of generating anti-therapeutic antibodies (ATA)

14 Murine mabs Form neutralizing human anti-mouse antibodies (HAMA) Muromonab-CD3 (OKT3) First generation mab of murine origin Treat acute transplant rejection 50% patients produced HAMA HAMA interferes OKT3 s binding to T-cells 14

15 Chimeric mabs Human constant regions and mouse variable regions Antigen specificity is the same as mouse antibodies Human Fc region make the in vivo half-life longer Induce human anti-chimeric antibodies (HACA) For infliximab (one chimeric mab), 61% patients had HACA response 15

16 Humanized mabs Only CDR(complementary determing region) is from murine; other parts are from human Produce human anti-human antibody (HAHA) For trastuzumab (a humanized mab), 0.1% patients have HAHA response 16

17 Human mabs Fully humanized mabs Production Phage display library Using transgenic XenoMouse with human heavy and light chain gene fragments Adalimumab, 5% patients produced HAHA 17

18 18 ttp:// einfach gross.jpg

Key structural components of MAbs Fv, Fragment variable V H V L scfv 19 http://www.mdpi.

19 Key structural components of MAbs Fv, Fragment variable V H V L scfv 19

20 Key structural components of MAbs Fab, Fragment antigen binding F(ab )2, two Fab s Fc F(ab )2 Fc 20

21 Modifying Fc mabs elicit cytotoxicity after Fc interact with its receptors (FcγR) and complement fixation CH2 domain or hinge region joining CH1 and CH2 are crucial regions for binding to FcγR Modify Fc regions can enhance or decrease the cytotoxity of mabs 21

Antibody derivatives and fusion proteins Fc have similar half life as fullsized antibody 22 Bind to a drug and reduce side effects of the drug F(ab

22 Antibody derivatives and fusion proteins Fc have similar half life as fullsized antibody 22 Bind to a drug and reduce side effects of the drug F(ab ) 2, Fab, scfv have short half life Fc is fused to cytokines, growth factor enzymes, etc., and used to increase half life and stability of cytokines

23 Outline Introduction to mabs Structure of mabs Therapeutic mechanism of mabs Preclinical and clinical assessments 23

24 Antibody, antigen, epitope Antibody 1 Antibody 4 Antigen Epitope Antibody 4 Antigen-binding sites Antibody

25 Therapeutic mechanism of mabs Direct modulation of target antigen Induction of cytotoxity (CDC and ADCC) Direct apoptosis 25

Direct modulation of target antigen Blocking and/or removal of target antigen E.g. anti-tnfα, anti-ige and anti-cd11a 26 http://www.

26 Direct modulation of target antigen Blocking and/or removal of target antigen E.g. anti-tnfα, anti-ige and anti-cd11a 26

27 Induction of cytotoxity: CDC Complement-Dependent Cytotoxicity Complement system mabs bind to receptor Form MAC Cell lysis 27

28 Induction of cytotoxity: ADCC Antibody-Dependent Cellular Cytotoxicity mabs bind to macrophage, monocyte or NK cells Trigger cell lysis The cells release cytokines, such as IFNγ 28

29 Direct apoptosis 29

30 Outline Introduction to mabs Structure of mabs Therapeutic mechanism of mabs Preclinical and clinical assessments 30

31 Preclinical and clinical assessments IND Investigational new drug application 研究性新药申请 BLA Biologics license application 生物制品许可申请 31

32 Pre-IND Mechanism of action In vitro and in vivo efficacy Safety pharmacology 安全药理 Toxicology / toxicokinetics (acute/repeat dose in relevant species) Tissue cross reactivity 组织交叉反应 Local tolerance 局部耐受 32

33 Post-IND Nonclinical General toxicity Clinical Safety and efficacy Characterization of dose-concentration effect relationship Material comparability studies Mechanistic modeling approach 33

34 Post-approval Post-marketing commitments 上市后的承诺 Safety assessment 34

relationship with humans 35 http://www.bio1000.

35 Preclinical safety assessment of mabs Most commonly used animals Cynomolgus and rhesus monkeys ( 猕猴和恒河猴 ) Close phylogenetic relationship with humans

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36 Preclinical safety assessment of mabs Use lower species Use analogous mabs Use transgenic models Express human receptor or target of interest azbkmqvqgcsw

37 Pharmacokinetics: Absorption mabs are not administrated orally, because of limited gastrointestinal stability, low lipophilicity, and size Intravenous administration is the most common route IM IC 37

38 Pharmacokinetics: Absorption Different injection methods IM injection, bioavailability ~60%, C max 0.96 μg/ml and T max 86 h IV injection, C max 3.1 μg/ml, T max 2.8 h Different species Greater bioavailability after SC injection in monkeys than in humans 38

39 Pharmacokinetics: Distribution The distribution of mabs is small Blood Extracellular spaces Target tissues The distribution of mabs depend on dose Saturation of the target antigen reduced the tissue distribution 39

40 Pharmacokinetics: Clearance Be broken down into peptide fragments and amino acids Antibodies fragments can treated by kidney 40

41 Summary Structure of mabs: Fc, Fab, V H, V L, C H, C L Function of mabs: direct modulation, induction of cytotoxity, direct apoptosis Pharmacokinetics: Absorption, distribution and clearance 41

42 Homework 10 Draw a scheme of mab structure and explain the function of different parts. What s the unique property of mab (compared to other protein drugs) in pharmacokinetics? 42

Pharmaceutical Biotechnology Lesson one

Pharmaceutical Biotechnology Lesson one Pharmaceutical Biotechnology Antibodies, vaccines and adjuvants By Yuqiong Xia 6/10/2017 生物技术制药 2 技术基础生物技术药物生物技术制药概念药物的开发药物的生产细胞因子生长因子激素类药物血液制品和治疗性酶抗体疫苗和佐剂核酸药物药物的发现专利的申请临床前试验临床试验生物药物的来源生物药物的生产和纯化生物药物的分析干扰素白介素造血生长因子