Novel High Affinity VEGF Analogs For Targeted Imaging of Thyroid Cancer

DESCRIPTION provided by applicant Thyroid cancer of follicular origin is the most common malignancy of endocrine tissues disproportionally affecting women and is one of the few cancers greatly increasing in incidence andamp prevalence for unknown reasons not solely attributable to improved diagnosis Most patients require lifelong diagnostic surveillance with radioiodine imaging to detect residual andamp recurrent tumor requiring subsequent therapy with I One of the PIs co invented andamp co developed Genzymeandapos s recombinant human TSH Thyrogen currently approved for enhancing diagnostic imaging with radioiodine and for stimulation of the thyroid cancer serum marker thyroglobulin TG However there is currently no optimal method to image the greatly increasing number of more aggressive cancers causing major morbidity and mortality detected by increased serum Tg but which have lost the ability to concentrate radioiodine because of decreased expression of the Na I symporter Nor is there any diagnostic method to predict which tumors may respond to increasingly important anti angiogenic therapy for these usually highly angiogenic tumors The two PIs have invented completely novel patented methods to design and produce much higher affinity and longer acting analogs of VEGF which can be used in novel targeted imaging of such tumors to the VEGFR receptor in both the stromal vascular endothelium and in tumor epithelium as supported by extensive and compelling preliminary data Two approaches of targeted imaging will be compared a direct optimized mTcm labeling method of such soluble VEGF analogs and another method using novel pegylated andamp VEGF analog targeted andquot stealthandquot nanoparticles which can selectively transverse the highly fenestrated leaky tumor vessels of angiogenic tumor vessels but not normal vessels In Phase of this SBIR fast track the PIs will Develop higher affinity and longer acting hVEGF analogs by lysine and arginine scanning mutagenesis of selected loops in both poles of the dimeric ligand without and with introduction of a novel neoglycosylation site adding two complex sialylated carbohydrate chains assessing binding of each analog to VEGFR and bioactivity in the stimulation of human vascular endothelial cell HUVEC proliferation produce and purify mg amounts of the final glycosylated and optimally sialylated analogs in CHO cells in roller bottles Develop novel pegylated polymeric andquot stealthandquot nanoparticles targeted by covalently coupled high affinity VEGF ligand and labeled with coupled radionuclides to high specific activity Assess in vitro binding and internalization of as wellas in vivo pharmacokinetic properties of VEGF analogs directly coupled to mTc or I compared to VEGF analog targeted labeled nanoparticles In Phase the PIs will Produce and purify large amounts mg of the final selected VEGF analog targeting candidates in a large mammalian cell bioreactor Greatly extend Phase in vivo and ex vivo imaging results by further optimizing imaging sensitivity and specificity Perform parallel quantitativ organ uptake studies with labeled VEGF analogs Make the final selection of the specific analog radionuclide and direct labeling versus indirect nanoparticle labeling method to bring forward for commercialization based on multiple criteria These completely novel methods for earlier detection andamp localization of the increasing numbers of aggressive thyroid cancers should lead to earlier and more personalized therapy predicting which patients will most benefit from increasingly important but potentially toxic anti angiogenic therapy PUBLIC HEALTH RELEVANCE Thyroid cancer of follicular origin is the most common malignancy of endocrine tissues and is increasing in incidence and prevalence for unknown reasons Most patients require lifelong diagnostic surveillance with radio iodine imaging to detect recurrent tumor and subsequent therapy with I However this approach only is applicable to differentiated thyroid cancers and there is currently no specific method of cancer imaging or any optimal method to treat more aggressive less differentiated cancers or those which have lost differentiation with time or repeated therapy The two PIandapos s have invented a completely novel and patented method to design and produce much higher affinity analogs of VEGF which can be used in both the targeted imaging and therapy of thyroid The targeted imaging will be achieved by an optimized labeling method of such novel VEGF analogs while the therapy will for the very first time utilize the power of nanotechnology to specifically target the cancer cells and not normal cells with tiny VEGF analog coated lipid particles These particles will be engineered to contain radio iodine or other imaging agent used as a prelude to subsequent targeted thyroid cancer therapy These completely novel and much improved methods for early detection of thyroid cancer followed by much improved and less toxic targeted therapy should lead to better outcomes including both survival and quality of life