Novel Long Acting rhTSH Superagonist Analogs for Improved Diagnostic Imaging, Thyroglobulin Stimulation and Therapy of Thyroid Cancer.

PROJECT SUMMARYABSTRACT Thyroid cancer is the most common malignancy of endocrine tissuesdisproportionally affecting womenand is one of the few cancers greatly increasing in incidence andampprevalence for unknown reasonsA very aggressive form of this cancer may result from nuclear accidents like Chernobyl andampFukushimaincreasing proximity of nuclear waste storage sitesor from nuclear explosions including those that could result from well publicized terrorist intentionsa vitally important andamptimely global health problemThough usually not fatalmost higher risk patients require lifelong diagnostic surveillance with radioiodine imaging to detect residual tumors requiring subsequent therapy withI to prevent severeoften underestimated morbidity andampless common mortalityOne of the PIsBWwhile an intramural lab chief at NIDDKco inventedco developed andamplicensed to Genzyme recombinant humanrh TSHThyrogenwith current annual sales over $MillionThyrogen is currently approved for enhancing imaging with radioiodinestimulation of the serum marker thyroglobulinTgandampnormal thyroid remnant ablationHoweverbecause of its short half life andamplack of equivalent stimulation to thyroid hormone withdrawal producing hypothyroidismThyrogen is not approved for thyroid cancer treatmentMoreoverthere is currently no method to image or treat the increasing number up toof much more aggressivemore radio resistant cancers which cause major morbidity and decreased quality of life not totally reflected in cancer mortality figuresThe PIs have previously invented a novelst andampnd generation superagonist analogs of rhTSHthe earliest non commercialized drug candidatesof higher potencyinitially licensed by the PIs from NIDDKThe current proposal is related to a totally novelrd generation analogthe proposed final drug candidatewith 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 andampvivo potencyas well as for thest time maximal efficacy in responsive andampradio resistant cancers with fewerless painful subcutaneous injectionswithout any toxicity or immunogenicityTRor TRgreatly superior to Thyrogenall previous Trophogen analogs andampwill allow greatly improved diagnosis and treatment of patients with thyroid cancerincluding many of those currently viewed as radio resistant for which there is no current therapyTrophogen analogsandampthus provides much superior patent protection for major commercialization advantages over Thyrogen and any possible future biosimilarsWe now provide compelling preliminary in vivo imaging andampthyroglobulinTgbiomarker stimulation data demonstrating the vast superiority of two newest analogs to Thyrogen andamptond generation analogs in normal thyroidas well as two novelhighly relevant xenograft tumor modelsWe believe these compelling preliminary in vivo imaging data in multiple animal models fully justify this fast track phaseSBIR proposalIn this submissionthe PIs propose PHASEAimEstablishment of stable CHO cell line providing high level expression of optimally neoglycosylated rhTSH superagonistsTRand TRsufficient for all future extensive animal studiesAimProduce andamppurify additional large quantities of TRand TRin roller bottles or bioreactors enough for all future extensive animal studies under good laboratory practicesGLPAimVerify superiority of GLP produced hTSH superagonists TRand TRto commercial wild type rhTSHThyrogen as well as to hypothyroidism from thyroid hormone withdrawal in selected rodent in vitro andampin vivo diagnostic radioiodine uptake andampin diagnostic serum thyroglobulinTgbiomarker levelsPHASEYearAimPerform subcutaneous andampintramuscular PK studies of TRand TRfrom optimized expressing CHO cell lines compared to Thyrogen and to endogenous TSH in hypothyroidism from thyroid hormone withdrawal in rodentsAimDevelop novel methodology and preliminary therapeutic data with limited dosing regimens in multiple differentiated thyroid cancer in vivo xenograft models such as tumor sizeapoptosis andamphistology to be used in yearto assess the totally novel commercial use of compare TRor TRin therapy of human thyroid cancerPHASEYearValidate superiority of TRor TRwith extensive dosing regimens to optimize amountnumber 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 andampTg secretionAimand with various therapeutic endpointsAimWe will also validate lack of immunogenicity of TRor TRwith mixed cultures of human lymphocytes of different HLA typesAimThese much more potentefficacious andamplongacting rhTSH analogs requiring fewerless painful subcutaneous injectionswill greatly improve diagnosisthyroid remnant ablation andampfor the first timeprovide a recombinant TSH even superior to currently required hypothyroidism in the treatment of thyroid cancerWe also project that with a new paradigm shifting therapy market sales should increase to $M y PROJECT NARRATIVE Thyroid cancer is the most common malignancy of endocrine tissuesis increasing in incidence and prevalenceand most higher risk patients require lifelong diagnostic surveillance with recombinant TSHstimulated radio iodine imaging to detect recurrent tumor and subsequent therapy withIHoweverthis approach currently has major limitations and many patients are unresponsive in both diagnosis and therapyThe PIs have invented a TSH analog that is much longer actingmuch more potenteffectiveand easier to administer with fewerless painful subcutaneous injections for both the diagnosis and treatment of thyroid cancer andampappears completely safe with no or minimal side effectsWe 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 $M y!