Recombinant Human

Recombinant human TSH (rec-hTSH; Thyrogen®, Genzyme) has been produced in a large-scale bioreactor using Chinese hamster ovary (CHO) cells stably transfected with TSH genes (Cole et al. 1993). Since CHO cells, unlike the pituitary thyrotroph cells, have no capacity to add penultimate ^-acetylgalactosamine or terminal sulfate, rec-hTSH is predominantly composed of oligosaccharide chains terminating in sialic acid. Rec-hTSH carbohydrate isoforms are similar to the sialylated forms of hTSH that are increased in primary hypothyroidism. Rec-hTSH has longer plasma halflife compared with normal pituitary hTSH. However, in several in vivo studies the bioactivity of rec-hTSH was found comparable to that of pituitary-derived hTSH (Cole et al. 1993; Szkudlinski et al. 1993; East-Palmer et al. 1995).

After cloning of human TSH beta gene (Wondisford et al. 1988) NIH researchers led by Bruce Weintraub initiated a collaborative research agreement with the Genzyme Corporation to produce and test rec-hTSH as a diagnostic agent to stimulate uptake in patients with differentiated thyroid carcinoma. An initial Phase I/II clinical trials showed that rec-hTSH is safe and efficacious in stimulating 1311 uptake and thyroglobulin secretion (Meier et al. 1994). Subsequent Phase III and confirmatory phase III trial with more than 100 patients indicated that rec-hTSH is almost as sensitive as conventional thyroid hormone withdrawal, but leads to considerable improvement of the quality of life because it avoids the symptoms of hypothyroidism (Ladenson et al. 1997). These major studies and case reports, including description of a patient with papillary thyroid carcinoma and hypopituitarism who had metastasis detected only after administration of rec-hTSH, exemplified the diagnostic potential of rec-hTSH (Ringel and Ladenson 1996). Thyrogen® has been approved by US FDA in 1998 for use in conducting thyroid scanning and thyroglobulin testing in the follow-up of patients with well differentiated thyroid carcinomas. Although many clinical studies demonstrated that the use ofrec-hTSH is an effective strategy to increase 1311 uptake, rec-hTSH is considered not entirely equivalent to endogenous hTSH induction by thyroid hormone withdrawal (Utiger 1997; Robbins et al. 2002; Emerson and Torres 2003). Therefore, novel recombinant hTSH analogs with enhanced bioactivity may become long awaited component of improved follow-up, ablation of remnants and metastases in differentiated thyroid carcinoma.

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