Microsoft PowerPoint - 10 Hematopoietic Growth Factor.pptx

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1 Pharmaceutical Biotechnology Hematopoietic Growth Factor By Yuqiong Xia 5/12/2017

2 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

3 造血过程造血过程概念血细胞概念造血生长因子白介素作为造血生长因子集落刺激因子白血病抑制因子促红细胞生成素血小板生成素 3

4 Keywords Red blood cell, white blood cell, lymphocyte, platelet, megakaryocyte, macrophage Hematopoietic growth factor (HGF), hematopoietic stem cells (HSC) G-CSF, GM-CSF, EPO, TPO, MGDF, SCF 4

5 Outline Concept of haemapoietic growth factor (HGF) Haemopoiesis Haemapoietic stem cells Blood cells Concept of HGF Common HGFs Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 5

6 Hematopoiesis Unsymmetrical division 西安电子科技大学 Lymphocyte 夏玉琼淋巴细胞红细胞血小板巨噬细胞定向祖细胞嗜碱性细胞嗜酸性细胞嗜中性细胞 6 Monocyte 单核细胞 Megakaryocyte 巨核细胞 /CH17%20Hematopoiesis.htm

7 夏玉琼 hematopoiesis = hemopoiesis ( 造血作用 ) 西安电子科技大学 The formation of blood Mediated by a series of growth factors The growth factors act individually and in various combinations stimulate the proliferation, differentiation, and function of hematopoietic cells 7

8 Outline Concept of haemapoietic growth factor (HGF) Haemopoiesis Haemapoietic stem cells Blood cells Concept of HGF Common HGFs Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 8

9 Stem cell 9

10 Types of Stem cells Embryonic stem cell Derived from embryos Adult stem cell (also called somatic stem cell) Concept: an undifferentiated cell, found among differentiated cells in a tissue or organ Function: to maintain and repair the tissue in which they are found 10

11 Embryonic stem cell 11

12 Adult stem cell From bone marrow Hematopoietic stem cells, forms all the types of blood cells in the body Bone marrow stromal stem cells, generate bone, cartilage, and fat cells From adult brain CNS stem cells, generate the brain's three major cell types: Astrocytes( 星细胞 ) and oligodendrocytes( 少突细胞 ), and nerve cells. 12

cell Epithelial cell Fat cell Neuron 13 Cardiac muscle

13 Adult stem cell Liver Bone Brain CNS stem cell Bone marrow Skeletol muscle Blood cell Blood vessel Bone marrow stromal cell Epithelial cell Fat cell Neuron 13 Cardiac muscle

14 Hematopoietic stem cells (HSC) Derive from mesoderm( 中胚层 ) Found in the bone marrow of adults, with large quantities in the pelvis, femur, and sternum( 盆骨股骨和胸骨 ). The umbilical cord blood ( 脐带血 ) A few in peripheral blood( 外周血 ) 14

15 How to get HSC from bone marrow Stem and progenitor cells( 祖细胞 ) can be taken from the pelvis( 盆骨 ), at the iliac crest( 髂骨 ), using a needle and syringe. 髂骨 15

16 How to get HSC from peripheral blood Inject a cytokine, such as granulocyte-colony stimulating factor (G-CSF) The cytokine induce cells to leave the bone marrow and circulate in the blood vessels Draw the blood 16

17 Outline Concept of haemapoietic growth factor (HGF) Haemopoiesis Haemapoietic stem cells Blood cells Concept of HGF Common HGFs Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 17

18 The constitution of blood 18

Red blood cell Also called erythrocyte D = 6.2-8.

19 Red blood cell Also called erythrocyte D = micrometers Lack cell nucleus Transport oxygen and carbon dioxide 19

20 White blood cell (WBC) Also called leukocytes Larger than RBC 7000 WBC per microliter blood ~1% of the blood volume Defend the body against both infectious diseases and foreign materials 20

21 Classifications of WBC Granulocytes 粒细胞 Neutrophil (most) Eosinophil (big particles) Basophil (least, < 0.6%) Agranulocytes 无颗粒的白细胞 Lymphocyte Monocyte (biggest WBC) 21

22 RBC vs. WBC RBC WBC Physical feature No nucleus, biconcave disc Nucleus with outer white buffer coat, irregular shape shaped Life span 120 days 4-30 days Type One Various Circulatory systems Counts in blood Function Cardiovascular systems Cardiovascular and lymphatic systems 36%-50% of blood 1% of blood Supply O 2 and transport CO Producing antibodies to develop immunity against infections

Platlet Platlet blood bag 23 http://simple.

23 Platelet Also called thrombocytes D = 2-3 micrometers Lead to formation of blood clot Platlet Platlet blood bag 23

24 Outline Concept of haemapoietic growth factor (HGF) Haemopoiesis Haemapoietic stem cells Blood cells Concept of HGF Common HGFs Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 24

25 Concept of HGFs Hematopoiesis is modulated by haemopoietic growthfactors 25

26 Outline Concept of haemapoietic growth factor (HGF) Haemopoiesis Haemapoietic stem cells Blood cells Concept of HGF Common HGFs Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 26

27 Outline Haemopoiesis Blood cells haemopoiesis Haemapoietic growth factor (HGF) Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 27

28 Interleukin as HGF (IL-3 and IL-11) IL-3 Stimulate the growth of immature precursors of all blood cells Clinical trials: stimulate production of blood cells in patients suffering from bone marrow failure induced by chemotherapy Produced by T cells, mast cells and eosinophils ( 嗜酸性粒细胞 ) 28

29 Interleukin as HGF (IL-3 and IL-11) IL-11 Stimulate production of platelets and growth/differentiation of bone marrow cells Application: Neumega (trade name) for prevention of thrombocytopenia ( 血小板缺少症 ) Produced in E. coli Purified in freee-dried format Excipients: phosphate buffer and glycine Produced by IL-1 activated bone marrow stromal cells and fibroblasts 29

30 Outline Haemopoiesis Blood cells haemopoiesis Haemapoietic growth factor (HGF) Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 30

31 Colony stimulating factor (CSF) Granulocyte colony-stimulating factor (G-CSF) 粒细胞集落刺激因子 Granulocyte macrophage colony-stimulating factor (GM-CSF) 粒细胞巨噬细胞集落刺激因子 31

32 G-CSF Also known as colony-stimulating factor 3 (CSF 3) Stimulate the production of granulocytes and stem cells Also stimulate the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils Produced by endothelium, macrophages, and a number of other immune cells 32

33 Therapeutic use of G-SCF To cancer patients To accelerate recovery from neutropenia (low levels of white blood cells) after chemotherapy To HSC donor To increase the number of hematopoietic stem cells To HSC receiver To compensate for conditioning regimens ( 预处理方案 the chemotherapy or irradiation given immediately prior to a transplant). 33

34 GM-CSF Stimulate the production of granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Secreted by macrophages, T cells, mast cells, NK cells, endothelial cells and fibroblasts. 34

35 Therapeutic use of GM-SCF To cancer patients Prevent neutropenia (low levels of white blood cells) following chemotherapy To HIV-infected patients A vaccine adjuvant, but not FDA approved 35

36 G-CSF and GM-CSF as drugs G-CSF On chromosome AA GM-CSF On chromosome or 128 AA Filgrastim ( 非格司亭 ) rhg-csf (G-CSF produced using recombinant DNA technology) Marketed by several companies rapidly absorbed after subcutaneous administration, achieving peak concentrations in 2 8 hours 36

37 Outline Haemopoiesis Blood cells haemopoiesis Haemapoietic growth factor (HGF) Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 37

38 西安电子科技大学夏玉琼 LIF (Leukaemia inhibitory factor 白血病抑制因子 ) Stimulate the differentiation of macrophages Promote enhanced platelet formation Prompt synthesis of acute phase proteins by the liver and promote increased bone reabsorption Produced by T cells, liver cells and fibroblasts 38

39 Outline Haemopoiesis Blood cells haemopoiesis Haemapoietic growth factor (HGF) Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 39

40 EPO (Erythropoietin) 促红细胞生成素 Stimulate the production of red blood cells by stem cells in the red bone marrow Produced mainly by the kidneys Released in response to decreased levels of oxygen detected in the blood 40

41 EPO(Erythropoietin) s (EPO) 促红细胞生成素 darbepoetin α 阿法达贝泊汀, threefold longer serum half-life in animal models compared with rhepo (whose half life is 4-13 h) 41

42 42

43 EPO 165 AA Require glycosylation for its in vivo biologic activity Two rhepo products are marketed and both are expressed in Chinese hamster ovary cells Epoetin α, in US, JAPAN, CHINA Epoetin β in US, JAPAN 43

44 Darbepoetin α 阿法达贝泊汀 Glycoengineered erythropoietin With more carbohydrate than rhepo With increased number of sialic acids ( 唾液酸 ) Sialic acids 44

45 Outline Haemopoiesis Blood cells haemopoiesis Haemapoietic growth factor (HGF) Interleukin as HGF Colony stimulating factor (CSF) LIF EPO TPO 45

46 Thrombopoietin (TPO) 促血小板生成素 Released by the liver, kidney and bone marrow in response to a reduction in circulating platelets Stimulate the differentiation of megakaryocyte lineage 46

47 TPO On chromosome 3, with AA 47

48 Summary Hematopoietic stem cell, red blood cells, white blood cells, platelet Hematopoiesis HGFs IL3 (all blood cells) and IL11 (platelet) G-CSF(granulocyte) and GM-CSF(granulocyte and monocyte) LIF(macrophage) EPO(RBC) TPO(platelet) 48

Microsoft PowerPoint - 11 Hematopoietic Growth Factor.pptx

Microsoft PowerPoint - 11 Hematopoietic Growth Factor.pptx Pharmaceutical Biotechnology Hematopoietic Growth Factor By Yuqiong Xia 2014 Keywords Hematopoietic growth factor (HGF), hematopoietic stem cells (HSC) Red blood cell, white blood cell, lymphocyte, platelet,