2013生物药物概况.ppt

Chapter 14 Group I: Protein therapeutics with enzymatic and regulatory activity p98,Box 1 | Functional classification of protein therapeutics，p91,Group I: protein therapeutics with enzymatic or regulatory activity Group II : protein therapeutics with special targeting activity Group III : protein vaccines Group IV : protein diagnostics,Group Ia ,p99,Replacing a protein that is deficient or abnormal (TABLES 1,2). Group Ia is dominated by endocrine and metabolic disorders with defined molecular etiologies . As more diseases are linked to deficiencies of specific proteins, this class will continue to grow.,Table1,2 ,p99,100,1.Endocrine disorders (hormone deficiencies) 2.Haemostasis and thrombosis 3.Metabolic enzyme deficiencies 4.Pulmonary and gastrointestinal-tract disorders 5.Immunodeficiencies 6.other,Group Ia Examples,p98-99,Insulin Lactase (乳糖酶) CFTR (cystic fibrosis transmembrane conductance regulator ) Fabry disease (mucopolysaccharidosis,黏多糖病, alpha galactosidase A ,) Factor VIII,Factor IX (凝血因子VIII 和IX),Cystic fibrosis,Cystic fibrosis (CF), is a hereditary disease that affects mainly the exocrine (mucus) glands of the lungs, liver, pancreas, and intestines, causing progressive disability due to multisystem failure.,Chloride Ion Channel,Lipase, Amylase Protease,Group Ib: Augmenting an existing pathway p1033,4).,Group Ib is dominated by therapies that augment haematological and endocrine pathways and immune responses. The many interferon and growth factor therapies in Group Ib effectively treat disease even when their precise pharmacological mechanism of action is unknown.,Group Ib examples,p101,Erythropoietin,EPO, TPO G-CSF GM-CSF Alteplase(tPA),enecteplase IL-11 IVF (FSH,HCG),G-CSF, Granulocyte colony-stimulating factor ) Filgrastim ,Neupogen,G-CSF , 175 aa ,MW18,800 Daltons NEUPOGEN is produced by Escherichia coli (E coli) bacteria into which has been inserted the human granulocyte colony-stimulating factor gene Because NEUPOGEN is produced in E coli, the product is nonglycosylated and thus differs from G-CSF isolated from a human cell.,GM-CSF, Granulocyte Macrophage colony-stimulating factor,127 aa,MW14434.5 GM-CSF stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. It is produced in yeast. FDA aproval 1991,Bayer, Sargramostim (marketed by Bayer under the tradename Leukine) is a recombinant granulocyte macrophage colony-stimulating factor which functions as a white blood cell growth factor.,Interleukin-11 (IL-11) (Neumega),IL-11: 178 aa,MW approximately 19,000 daltons Neumega, the polypeptide is 177 amino acids in length and differs from the 178 amino acid length of native IL-11 only in lacking the amino-terminal proline residue. This alteration has not resulted in measurable differences in bioactivity either in vitro or in vivo.,tPA Tissue Plasminogen Activator,P101,Administration of t-PA (Activase) in,ACUTE ISCHEMIC STROKE,SYSTEMIC (ARTERIAL) EMBOLI, 85% arise from the heart,Embolization of the limbs, brain, eye, and viscera.,Often cause infarcts.,Kidney,Limbs,Brain,Spleen,Heart,HEMOSTASIS,Coagulation Proteins,Vascular Wall,Platelets,Bleeding or thrombosis can result from quantitative or qualitative abnormalities of platelets or coagulation proteins, as well as, vessel wall abnormalities.,Fibrin,Fibrin Split Products (FSP),Plasmin,Plasminogen,tPA,Fibrinolysis,What is Tissue Plasminogen Activator (t-PA)?,t-PA is an enzyme that serves in the cascade of events leading to dissolution of blood clots,Plasminogen,Damaged Tissues,Thrombolytic Agents,1st generation: Streptokinase Urokinase 2nd generation: Pro-urokinase Alteplase (recombinant tissue plasminogen activator rtPA),Thrombolytic Agents,3rd generation: Reteplase Lanoteplase Tenecteplase (TNK),tPA: Molecular and Biochemical Properties,NH2,HOOC,EGF,Finger,Kringle 1,Kringle 2,Domain functions,The finger region is responsible for the high affinity fibrin binding (fibronectin finger ). The epidermal growth factor region contributes to liver plasma clearance. Kringle 1 is associated with receptor binding and contributes in a major way to fibrin specificity. Additionally, kringle 1 is involved in plasma clearance. The kringle 2 region is involved in low-affinity fibrin binding. Protease domain is the site of enzymatic activity that cleaves the plasminogen to plasmin. PAI-1 inhibition takes place here.,Fibrin Specificity,Molecular Structures of Fibrinolytics,TNK t-PA (tenecteplase) r-PA (reteplase),t-PA (alteplase) n-PA (lanoteplase),TNK-tPA: Molecular and Biochemical Properties,K Domain Ala-Ala-Ala-Ala for Lys-His-Arg at 296-299: More resistant to PAI 1, enzyme which breaks down lytic agents,NH2,HOOC,EGF,Finger,Kringle 1,Kringle 2,T Domain Asn for Thr at 103: Reduces clearance; single bolus,N Domain Gln for Asn at 117 : Increased fibrin specificity,The name TNK reflects the fact that three domains (the T, N, and K domains) have been altered. The TNK-tPA molecule includes 3 substitution mutations, which enhance its fibrin specificity, prolong its half-life, and greatly increase resistance to PAI-1. At the T domain, threonine is replaced with asparagine on kringle 1 resulting in slower plasma clearance and thus, a longer half-life compared with t-PA. At the N domain, glutamine is substituted for asparagine on kringle 1 resulting in increased fibrinolytic activity and fibrin binding.,At the K domain, Lys-His-Arg are replaced with four alanines substitutions result in increased fibrin specificity and an 80-fold increase in resistance to PAI-1. The end result is a molecule with a prolonged half-life (approximately 20 minutes), increased fibrin specificity, and an 80-fold resistance to PAI-1.,Group Ic,p107,Providing a novel function or activity (TABLE 5). Group Ic demonstrates the rational use of naturally occurring proteins to modify the pathophysiology of human diseases. The future growth of this class depends on understanding protein function in human physiology as well as protein function in other organisms.,Occasionally, the activity of a particular protein is desirable even though the body does not normally express that activity. Protein therapeutics that we have classified in Group Ic cont