This book contains a selection of the papers presented at the meeting "Between Clone and Clinic" which was organised in March 1990 in Amsterdam by the dutch Organisation for Applied Research, TNO, and the University of Utrecht. The scope of this meeting was the development of biotechnological pharmaceuticals mainly made by recombinant DNA technology or monoclonal antibody techniques. All aspects concerning the development of the products after host cells producing them are obtained where discussed. The meeting was attended by twohundred specialists from all over the globe, including phar macologists, toxicologists, registration experts, Quality Assurence managers, production en gineers and physicians. Biotechnological pharmaceuticals are in general large and complex protein molecules. Bringing these products to the market poses other problems than encountered with the classical chemical drugs. The source of biotechnological pharmaceuticals are living cells. The function of cells are depend ent on many factors and the stability of production may be a problem. Good Laboratory and Manufactory Practices with Quality Control (GLP and GMP) are of paramount importance and are discussed in a number of papers. The products of the new biotechnology are often highly specific and only active in the human species. Also the side effects can only be studied in the clinical setting. Even when the product is active in animals there is the problem of antigenicity. During treatment the animals will produce antibodies which neutralise the activity. So safety testing may prove difficult.
One: Registration, Toxicity and Quality Control.- 1. Toxicity testing of rDNA products.- 2. Experiences with the EC “high tech” procedure.- 3. The regulation of pharmaceuticals: philosophy and principles.- 4. Quality control of vaccines.- 5. Regulatory affairs and biotechnology in Europe: the CPMP “high tech” and multistate procedures.- 6. Formulating biotechnology products.- 7. Development of analytical methods for monitoring the stability of antibody formation by hybridoma cells in continuous culture systems.- Two: Monoclonal Antibodies.- 8. Toward human monoclonal antibodies.- 9. Biodistribution, binding and internalisation of monoclonal antibodies to human ovarian carcinoma cells.- 10. Pharmacokinetics and tissue distribution of Indium-111-labeled OV-TL 3 F(ab’)2 in ovarian cancer patients.- 11. Characterization of human monoclonal antibodies specific for the rabies virus.- 12. Biochemical and immunological evaluation of an anti-fibrin monoclonal antibody complex containing T2Gls Fab’ intended for imaging venous thrombi.- 13. Monoclonal antibodies in radioimmunoscintigraphy. Some hurdles between clone and clinic.- 14. Clinical relevance of the tumor marker CA 15.3 in the management of cancer patients.- 15. Practical applications of monoclonal antibodies against polymorphic epithelial mucin in the differential diagnosis of human tumors.- 16. Selection of monoclonal anti-digoxin antibodies suitable for monitoring of cardiac glycosides.- 17. Diagnostic use of anti-modified nucleoside monoclonal antibodies.- 18. Monoclonal antibodies radiolabeled with different radioisotopes for biodistribution and radioimmunodetection of tumor xenografts in the nude rat.- 19. Bispecific monoclonal antibody (BIAB)-retargeted cellular therapy for local treatment of cancer patients.- 20. Enhanced binding of t-PA to fibrin using bispecific monoclonal antibodies.- 21. Recent developments and perspectives on the future of human and murine monoclonal antibodies in the diagnosis and treatment of cancer.- 22. Pharmacokinetics and safety of a human IGM antibody, HA-1A.- 23. Development and clinical experience with humanised monoclonal antibodies.- 24. A method for the transformation of hybridoma cell lines with improved efficiency: its use in the production of bispecific monoclonal antibodies.- 25. To an optimal design of an airlift bioreactor for the cultivation of hybridomas.- Three: Marketed Products.- 26. Experience with marketed biotech products: rt-PA.- 27. Clinical trial of recombinant human IL-2 in the treatment of Mycobacterium Avium complex infection.- 28. Use of recombinant human erythropoietin in anemic dialysis patients.- 29. Experience with biosynthetic growth hormone.- Four: New Products.- 30. Recombinant follicle stimulating hormone. I. Construction, selection and characterization of a cell line.- 31. Recombinant human follicle stimulating hormone. II. Biochemical and biological characteristics.- 32. Heterologous expression of human Interleukin-3.- 33. Purification of recombinant human Interleukin-3 from Bacillus Licheniformis.- 34. The acid- and thermolabile interferon alpha: a subtype, or a new cell inhibitor?.- 35. The IFN? receptor as tool for the discovery of new immunomodulatory drugs.- 36. Cloned receptors and transfected cell lines in the design of new drugs: muscarinic cholinergic receptors.- Five: Drug Delivery.- 37. Structural analysis of carbohydrate chains of native and recombinant-DNA glycoproteins.- 38. The role of protein structure in surface tension kinetics.- 39. Antigen carriers: a success determining factor for subunit vaccines?.- 40. Intranasal delivery of insulin: absorption enhancement by the fusidate derivative STDHF in rabbits and rats and effects on human nasal ciliary movement in vitro.- 41. Improved oral peptide delivery by means of mucoadhesion.- 42. Delivery of therapeutic peptides and proteins.- 43. Compatibility studies of a soluble T4 receptor with a microinfusion pump for continuous intravenous therapy.- 44. Immunoliposome-mediated delivery of chemotherapeutics.- 45. A novel approach for the selection and detection of cells transfected with adenosine deaminase expression vectors.- 46. Toward gene therapy in hemophilia A: introduction of factor VIII expression vectors into somatic cells.