BIOSYNTHESIS, GLYCOSYLATION, AND ACTION OF THYROTROPIN--CLINICAL TRIALS OF TSH

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Recombinant thyrotropin has been produced by novel methods of transient or stable transfection of alpha and hTSH beta minigenes into Chinese hamster ovary cells. Utilizing products produced in a large scale bioreactor as well as a hollow fiber bioreactor, we have been able to purify several hundred milligrams of this product. Terminal sialylation of recombinant TSH determines in vitro and in vivo bioactivity as well as clearance rate. The carbohydrate structure of recombinant TSH has been characterized in detail and differs from pituitary TSH. Through a Cooperative Research and Development Agreement with the Genzyme Corporation (Boston), recombinant human TSH is being used for clinical studies in patients with thyroid cancer. This product is expected to stimulate uptake of radioactive iodine for both diagnostic and therapeutic purposes and to obviate the need for performing uptake studies in hypothyroid patients. An Investigational New Drug Application has been approved by the Food and Drug Administration and phase I and II clinical trials have been completed at NIH and 4 other medical center showing preliminary efficacy and safety in 19 patients. Phase III trials at NIH and 11 other medical centers involving over 100 patients are currently near completion. Currently we have developed a second generation long acting TSH analog in which a chimeric beta subunit has been engineered.