SBIR-STTR Award

Thyroid cancer is the most common malignancy of endocrine tissues, disproportionally affecting women, and is one of the few cancers greatly increasing in incidence & prevalence for unknown reasons. A very aggressive form of this cancer may result from nuclear accidents like Chernobyl & Fukushima, increasing proximity of nuclear waste storage sites, or from nuclear explosions including those that could result from well-publicized terrorist intentions, a vitally important & timely global health problem. Though usually not fatal, most higher risk patients require lifelong diagnostic surveillance with radioiodine imaging to detect residual tumors requiring subsequent therapy with 131I to prevent severe, often underestimated morbidity & less common mortality. One of the PIs (BW), while an intramural lab chief at NIDDK, co-invented, co-developed & licensed to Genzyme recombinant human (rh)TSH (Thyrogen), with current annual sales over $200 Million. Thyrogen is currently approved for enhancing imaging with radioiodine, stimulation of the serum marker thyroglobulin (Tg), & normal thyroid remnant ablation. However, because of its short half-life & lack of equivalent stimulation to thyroid hormone withdrawal producing hypothyroidism, Thyrogen is not approved for thyroid cancer treatment. Moreover, there is currently no method to image or treat the increasing number up to 20% of much more aggressive, more radio-resistant cancers which cause major morbidity and decreased quality of life not totally reflected in cancer mortality figures. The PIs have previously invented a novel 1st & 2nd generation superagonist analogs of rhTSH, the earliest non-commercialized drug candidates, of higher potency, initially licensed by the PIs from NIDDK. The current proposal is related to a totally novel 3rd generation analog, the proposed final drug candidate, with greatly increased half-life achieved with a totally novel dual neoglycosylation insert that for the first time synergizes with the superagonist mutations to achieve much higher in vitro & vivo potency, as well as for the 1st time maximal efficacy in responsive & radio-resistant cancers with fewer, less painful subcutaneous injections, without any toxicity or immunogenicity. TR14601 or TR14701 greatly superior to Thyrogen, all previous Trophogen analogs & will allow greatly improved diagnosis and treatment of patients with thyroid cancer, including many of those currently viewed as radio-resistant for which there is no current therapy. Trophogen analogs, & thus provides much superior patent protection for major commercialization advantages over Thyrogen and any possible future biosimilars. We now provide compelling preliminary in vivo imaging & thyroglobulin (Tg) biomarker stimulation data demonstrating the vast superiority of two newest analogs to Thyrogen & to 2nd generation analogs in normal thyroid, as well as two novel, highly relevant xenograft tumor models. We believe these compelling preliminary in vivo imaging data in multiple animal models fully justify this fast track phase 1-2 SBIR proposal. In this submission, the PIs propose PHASE 1 Aim 1: Establishment of stable CHO cell line providing high level expression of optimally neoglycosylated rhTSH superagonists (TR14601 and TR14701) sufficient for all future extensive animal studies; Aim 2: Produce & purify additional large quantities of TR14601 and TR14701 in roller bottles or bioreactors enough for all future extensive animal studies under good laboratory practices (GLP); Aim 3: Verify superiority of GLP-produced hTSH superagonists TR14601 and TR14701 to commercial wild type rhTSH, Thyrogen as well as to hypothyroidism from thyroid hormone withdrawal in selected rodent in vitro & in vivo diagnostic radioiodine uptake & in diagnostic serum thyroglobulin (Tg) biomarker levels. PHASE 2 (Year 1) Aim 1: Perform subcutaneous & intramuscular PK studies of TR 14601 and TR14701 from optimized expressing CHO cell lines compared to Thyrogen and to endogenous TSH in hypothyroidism from thyroid hormone withdrawal in rodents; Aim 2: Develop novel methodology and preliminary therapeutic data with limited dosing regimens in multiple differentiated thyroid cancer in vivo xenograft models such as tumor size, apoptosis & histology to be used in year 2 to assess the totally novel commercial use of compare TR14601 or TR14701 in therapy of human thyroid cancer. PHASE 2 (Year 2) Validate superiority of TR14601 or TR14701 with extensive dosing regimens to optimize amount, number and intervals of injections compared to both Thyrogen and to hypothyroidism from thyroid hormone withdrawal in multiple differentiated thyroid cancer in vivo xenograft models of diagnostic radioiodine uptake & Tg secretion (Aim 1) and with various therapeutic endpoints (Aim 2). We will also validate lack of immunogenicity of TR14601 or TR14701 with mixed cultures of human lymphocytes of different HLA types (Aim 3). These much more potent, efficacious & long- acting rhTSH analogs requiring fewer, less painful subcutaneous injections, will greatly improve diagnosis, thyroid remnant ablation &, for the first time, provide a recombinant TSH even superior to currently required hypothyroidism in the treatment of thyroid cancer. We also project that with a new paradigm-shifting therapy market sales should increase to $500+ M/y.

Public Health Relevance Statement:
PROJECT NARRATIVE Thyroid cancer is the most common malignancy of endocrine tissues, is increasing in incidence and prevalence, and most higher risk patients require lifelong diagnostic surveillance with recombinant TSH- stimulated radio-iodine imaging to detect recurrent tumor and subsequent therapy with 131I. However, this approach currently has major limitations and many patients are unresponsive in both diagnosis and therapy. The PIs have invented a TSH analog that is much longer-acting, much more potent, effective, and easier to administer with fewer, less-painful subcutaneous injections for both the diagnosis and treatment of thyroid cancer & appears completely safe with no or minimal side effects. We expect this new analog to revolutionize the diagnosis and treatment of thyroid cancer with a new paradigm-shifting therapy market that should increase sales to $500+ M/y!.

Project Terms:
Ablation; Adverse effects; Affect; analog; Animal Model; Animals; Apoptosis; Biological Markers; Bioreactors; cancer diagnosis; cancer therapy; Cell Line; Chinese Hamster Ovary Cell; Clinical; commercialization; Complementary DNA; Data; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Dose; drug candidate; Endocrine; Explosion; Fukushima; Future; Generations; global health; good laboratory practice; Half-Life; high risk; Histology; Human; Hypothyroidism; Image; Image Enhancement; immunogenicity; improved; In Vitro; in vivo; in vivo imaging; Incidence; Injections; Intramuscular; Legal patent; Lymphocyte; Malignant neoplasm of thyroid; Malignant Neoplasms; Methodology; Methods; Modeling; Morbidity - disease rate; mortality; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; novel; Nuclear; Nuclear Accidents; Pain; Patient risk; Patients; Phase; Prevalence; prevent; Quality of life; Radioactive Iodine; Radioactive Waste; radioiodine imaging; radioresistant; Recombinants; Recurrent tumor; Regimen; Residual Tumors; Rodent; Roller Bottle; Sales; Serum; Serum Markers; Site; Small Business Innovation Research Grant; subcutaneous; Subcutaneous Injections; Therapeutic; Thyroglobulin; Thyroid Gland; Thyroid Hormones; Time; Tissues; Toxic effect; tumor; tumor xenograft; United States National Institutes of Health; uptake; Withdrawal; Woman; Xenograft Model

Thyroid cancer is the most common malignancy of endocrine tissues, disproportionally affecting women, and is one of the few cancers greatly increasing in incidence & prevalence for unknown reasons. A very aggressive form of this cancer may result from nuclear accidents like Chernobyl & Fukushima, increasing proximity of nuclear waste storage sites, or from nuclear explosions including those that could result from well-publicized terrorist intentions, a vitally important & timely global health problem. Though usually not fatal, most higher risk patients require lifelong diagnostic surveillance with radioiodine imaging to detect residual tumors requiring subsequent therapy with 131I to prevent severe, often underestimated morbidity & less common mortality. One of the PIs (BW), while an intramural lab chief at NIDDK, co-invented, co-developed & licensed to Genzyme recombinant human (rh)TSH (Thyrogen), with current annual sales over $200 Million. Thyrogen is currently approved for enhancing imaging with radioiodine, stimulation of the serum marker thyroglobulin (Tg), & normal thyroid remnant ablation. However, because of its short half-life & lack of equivalent stimulation to thyroid hormone withdrawal producing hypothyroidism, Thyrogen is not approved for thyroid cancer treatment. Moreover, there is currently no method to image or treat the increasing number up to 20% of much more aggressive, more radio-resistant cancers which cause major morbidity and decreased quality of life not totally reflected in cancer mortality figures. The PIs have previously invented a novel 1st & 2nd generation superagonist analogs of rhTSH, the earliest non-commercialized drug candidates, of higher potency, initially licensed by the PIs from NIDDK. The current proposal is related to a totally novel 3rd generation analog, the proposed final drug candidate, with greatly increased half-life achieved with a totally novel dual neoglycosylation insert that for the first time synergizes with the superagonist mutations to achieve much higher in vitro & vivo potency, as well as for the 1st time maximal efficacy in responsive & radio-resistant cancers with fewer, less painful subcutaneous injections, without any toxicity or immunogenicity. TR14601 or TR14701 greatly superior to Thyrogen, all previous Trophogen analogs & will allow greatly improved diagnosis and treatment of patients with thyroid cancer, including many of those currently viewed as radio-resistant for which there is no current therapy. Trophogen analogs, & thus provides much superior patent protection for major commercialization advantages over Thyrogen and any possible future biosimilars. We now provide compelling preliminary in vivo imaging & thyroglobulin (Tg) biomarker stimulation data demonstrating the vast superiority of two newest analogs to Thyrogen & to 2nd generation analogs in normal thyroid, as well as two novel, highly relevant xenograft tumor models. We believe these compelling preliminary in vivo imaging data in multiple animal models fully justify this fast track phase 1-2 SBIR proposal. In this submission, the PIs propose PHASE 1 Aim 1: Establishment of stable CHO cell line providing high level expression of optimally neoglycosylated rhTSH superagonists (TR14601 and TR14701) sufficient for all future extensive animal studies; Aim 2: Produce & purify additional large quantities of TR14601 and TR14701 in roller bottles or bioreactors enough for all future extensive animal studies under good laboratory practices (GLP); Aim 3: Verify superiority of GLP-produced hTSH superagonists TR14601 and TR14701 to commercial wild type rhTSH, Thyrogen as well as to hypothyroidism from thyroid hormone withdrawal in selected rodent in vitro & in vivo diagnostic radioiodine uptake & in diagnostic serum thyroglobulin (Tg) biomarker levels. PHASE 2 (Year 1) Aim 1: Perform subcutaneous & intramuscular PK studies of TR 14601 and TR14701 from optimized expressing CHO cell lines compared to Thyrogen and to endogenous TSH in hypothyroidism from thyroid hormone withdrawal in rodents; Aim 2: Develop novel methodology and preliminary therapeutic data with limited dosing regimens in multiple differentiated thyroid cancer in vivo xenograft models such as tumor size, apoptosis & histology to be used in year 2 to assess the totally novel commercial use of compare TR14601 or TR14701 in therapy of human thyroid cancer. PHASE 2 (Year 2) Validate superiority of TR14601 or TR14701 with extensive dosing regimens to optimize amount, number and intervals of injections compared to both Thyrogen and to hypothyroidism from thyroid hormone withdrawal in multiple differentiated thyroid cancer in vivo xenograft models of diagnostic radioiodine uptake & Tg secretion (Aim 1) and with various therapeutic endpoints (Aim 2). We will also validate lack of immunogenicity of TR14601 or TR14701 with mixed cultures of human lymphocytes of different HLA types (Aim 3). These much more potent, efficacious & long-acting rhTSH analogs requiring fewer, less painful subcutaneous injections, will greatly improve diagnosis, thyroid remnant ablation &, for the first time, provide a recombinant TSH even superior to currently required hypothyroidism in the treatment of thyroid cancer. We also project that with a new paradigm-shifting therapy market sales should increase to $500+ M/y.

Public Health Relevance Statement:
Thyroid cancer is the most common malignancy of endocrine tissues, is increasing in incidence and prevalence, and most higher risk patients require lifelong diagnostic surveillance with recombinant TSH- stimulated radio-iodine imaging to detect recurrent tumor and subsequent therapy with 131I. However, this approach currently has major limitations and many patients are unresponsive in both diagnosis and therapy. The PIs have invented a TSH analog that is much longer-acting, much more potent, effective, and easier to administer with fewer, less-painful subcutaneous injections for both the diagnosis and treatment of thyroid cancer & appears completely safe with no or minimal side effects. We expect this new analog to revolutionize the diagnosis and treatment of thyroid cancer with a new paradigm-shifting therapy market that should increase sales to $500+ M/y!.

NIH Spending Category:
Biomedical Imaging; Biotechnology; Cancer

Project Terms:
Ablation; Affect; analog; Animal Model; Animals; Apoptosis; Biological Markers; Bioreactors; cancer diagnosis; cancer therapy; Cell Line; Chernobyl Nuclear Accident; Chinese Hamster Ovary Cell; Clinical; commercialization; Complementary DNA; Data; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Dose; drug candidate; Endocrine; Explosion; Fukushima; Future; Generations; global health; good laboratory practice; Half-Life; high risk; Histology; Human; Hypothyroidism; Image; Image Enhancement; immunogenicity; improved; In Vitro; in vivo; in vivo imaging; Incidence; Injections; Intramuscular; Legal patent; Lymphocyte; Malignant neoplasm of thyroid; Malignant Neoplasms; Methodology; Methods; Modeling; Morbidity - disease rate; mortality; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; novel; Nuclear; Nuclear Accidents; off-patent; Pain; Patients; Phase; Prevalence; prevent; Quality of life; Radioactive Iodine; Radioactive Waste; radioiodine imaging; radioresistant; Recombinants; Recurrent tumor; Regimen; Residual Tumors; Rodent; Roller Bottle; Sales; Serum; Serum Markers; side effect; Site; Small Business Innovation Research Grant; subcutaneous; Subcutaneous Injections; Therapeutic; Thyroglobulin; Thyroid Gland; Thyroid Hormones; Time; Tissues; Toxic effect; tumor; tumor xenograft; United States National Institutes of Health; uptake; Withdrawal; Woman; Xenograft Model