Future Perspectives Of Tsh Analogs

The Natural Thyroid Diet

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The opportunities and challenges facing clinical development ofrec-hTSH analogs are now being realized more clearly. (wild-type recombinant human TSH)

produced in Chinese hamster ovary cells exhibits relatively low affinity to the TSH receptor that translates into limited clinical efficacy. Despite quite apparent advantages of TSH superactive analogs, further development and clinical trails of such analogs are now dependent on commitment of biotech industry for a relatively small "thyroid market" (Table 2).

Table 2. Potential uses of superactive analogs of TSH

Clinical Differentiated thyroid cancer follow-up (TSH analog stimulated thyreoglobulin testing and radioiodinc scanning) Differentiated thyroid cancer treatment (TSH analog induced radioiodinc ablation) Large euthyroid goiter treatment (TSH analog induced radioiodinc ablation) TSH analog stimulation tests (testing thyroid reserve, identifying "warm" thyroid nodules, detecting thyroid hemiagenesis, etc.) Management of patients with TSH receptor mutations associated with low ligand binding, impaired receptor expression or coupling TSH receptor-mediated delivery of therapeutic agents to the thyroid cancer cell (Figure 5)

Laboratory ' I hTM I analog in TSH binding inhibition (TBI) assay for autoantibodies to the TSH rcccptor (Kakinuma et al. 1997) and immunoassays (Ribela et aL 1996) TSH analog-stimulated thyroglobulin (Tg) mKNA testing in thyroid cancer patients with positive or negative anti-Tg antibodies

Basic Science Structure-function studies of TSH-TSH receptor interaction, studies ofTSH receptors in non-thyroidal tissue (Szkudlinski et al. 2002)

Retrovirus expressing NIS, TSHR, toxins, p53

Figure 5. TSH receptor-mediated delivery of various therapeutic agents to the thyroid cancer cell. One of many possible scenarios includes restoration of cancer cell differentiation using high affinity interaction between TSH analog and largely depleted pool of TSH receptors. Another approach involves TSH analog-mediated targeted killing of thyrocyte originated carcinomas. TSHR, TSH receptor, NIS, sodium iodide symporter.

Figure 5. TSH receptor-mediated delivery of various therapeutic agents to the thyroid cancer cell. One of many possible scenarios includes restoration of cancer cell differentiation using high affinity interaction between TSH analog and largely depleted pool of TSH receptors. Another approach involves TSH analog-mediated targeted killing of thyrocyte originated carcinomas. TSHR, TSH receptor, NIS, sodium iodide symporter.

Since structural data on TSH receptor and other G protein-coupled receptors (GPCRs) are very limited, designing small molecules binding to TSH receptor that do not bind to non-targeted receptors poses a major problem. Although GPCR microar-rays may narrow the number of useful agonistic compounds it is not clear if selected small molecule can be devoid of aberrant binding to other receptors that can lead to serious side effects (Fang et al. 2003). Therefore, TSH and TSH receptor structure based analogs appear far more promising. Recent studies on the mechanism of TSH receptor activation and their constitutive activity provide additional leads for the design of high affinity antagonist and inverse agonists (Gudermann et al. 1996; Zhang et al. 2000; Wonerow et al. 2001; Rodien et al. 2003).

Interestingly, another member of glycoprotein hormone family—thyrostimulin was recently identified by comparative genomic analysis (Hsu et al. 2002) and shown to be capable of activating TSH receptor (Nakabayashi et al. 2002). Structure-function studies of thyrostimulin and its analogs should provide new insights into mechanism of TSH receptor activation. Although, the intrinsic bioactivity of highly purified thyros-timulin should be studied in more details, it is possible that third or fourth generation TSH analogs will include TSH-thyrostimulin chimeras with their respective superactive components.

Current research, development pipelines and clinical trials in progress clearly suggest that the decade of recombinant proteins with a native amino acid sequence is coming to an end. The pharmaceutical industry and biotechnology companies are increasingly exploring new types of engineered proteins including superactive hormones. Diagnostic and therapeutic use of such engineered hormones with improved characteristics, tailored to specific patient needs (long and short acting variants) should represent an important milestone in medicine of 21st century.

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