Trifunctional constructs with tunable pharmacokinetics useful in imaging and anti-tumor therapies

Abstract

The present technology provides compounds, as well as compositions including such compounds, useful for imaging and/or treatment of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary, gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and/or a prostate cancer.

What is claimed is: 
     
         1 . A composition comprising: a tumor-binding domain, an albumin-binding domain, and an imaging agent-containing domain, wherein the tumor-binding domain comprises an active site that is distal to and sterically unimpeded by the albumin-binding domain and the imaging agent-containing domain, and the relative affinity of the tumor-binding domain and the albumin-binding domain differ in specific affinity by a factor of at least 100 to about 10,000. 
     
     
         2 . The compound of  claim 1 , wherein the tumor-binding domain binds to a tumor associated molecular target selected from one or more of a tumor-specific cell surface protein, prostate specific membrane antigen (PSMA), somatostatin peptide receptor-2 (SSTR2), alphavbeta3 (αvβ3), alphavbeta6, a gastrin-releasing peptide receptor, a seprase, fibroblast activation protein alpha (FAP-alpha), an incretin receptor, a glucose-dependent insulinotropic polypeptide receptor, VIP-1, NPY, a folate receptor, LHRH, a neuronal transporter (e.g., noradrenaline transporter (NET)), EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2, TF antigen, an endothelial specific marker, neuropeptide Y, uPAR, TAG-72, a claudin, a CCK analog, VIP, bombesin, VEGFR, a tumor-specific cell surface protein, GLP-1, CXCR4, Hepsin, TMPRSS2, a caspace, cMET, or an overexpressed peptide receptor. 
     
     
         3 . The compound of  claim 2 , wherein the tumor-binding domain binds to the tumor associated molecular target with moderate to high affinity. 
     
     
         4 . The compound of  claim 1 , wherein the imaging agent-containing domain further comprises an imaging isotope. 
     
     
         5 . A compound comprising: a multi-targeted agent having a plurality of sterically unimpeded targeting domains, comprising a first targeting domain comprising a blood-protein binding domain having specific affinity for binding human serum albumin in the range of about 0.25 to 50 micromolar, and a second targeting domain comprising a tumor-binding domain having specific affinity for a tumor associated molecular target in the range of about 0.1 to 75 nanomolar; wherein the relative affinities of the first and second targeting domains differ in specific affinity by a factor of at least 100 to about 10,000; and an imaging agent-containing domain comprising a positron-emitting isotope. 
     
     
         6 . The compound of  claim 5 , wherein the tumor associated molecular target is selected from one or more of a tumor-specific cell surface protein, prostate specific membrane antigen (PSMA), somatostatin peptide receptor-2 (SSTR2), alphavbeta3 (αvβ3), alphavbeta6, a gastrin releasing peptide receptor, a seprase, fibroblast activation protein alpha (FAP-alpha), an incretin receptor, a glucose-dependent insulinotropic polypeptide receptor, VIP-1, NPY, a folate receptor, LHRH, a neuronal transporter (e.g., noradrenaline transporter (NET)), EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2, TF-antigen, an endothelial specific marker, neuropeptide Y, uPAR, TAG-72, a claudin, a CCK analog, VIP, bombesin, VEGFR, a tumor-specific cell surface protein, GLP-1, CXCR4, Hepsin, TMPRSS2, a caspace, cMET, or an overexpressed peptide receptor. 
     
     
         7 . The compound of  claim 6 , wherein the tumor-binding domain binds to the tumor associated molecular target with moderate to high affinity. 
     
     
         8 . The compound of  claim 5 , wherein the positron-emitting isotope is  18 F or  68 Ga. 
     
     
         9 . A compound comprising: a multi-targeted agent having a plurality of sterically unimpeded targeting domains comprising, a first targeting domain comprising a blood-protein binding domain having specific affinity for binding human serum albumin in the range of about 0.25 to 50 micromolar, a second targeting domain comprising a tumor-binding domain having specific affinity for fibroblast activation protein alpha (FAP-alpha) in the range of about 0.1 to 75 nanomolar; wherein the relative affinities of the first and second targeting domains differ in specific affinity by a factor of at least 100 to about 10,000; and an imaging agent-containing domain. 
     
     
         10 . The compound of  claim 9 , wherein the blood-protein binding domain binds human serum albumin with an affinity in the range of about 0.4 to 20 micromolar, and the tumor-binding domain binds FAP-alpha with an affinity in the range of about 0.1 to 15 nanomolar; wherein the relative affinities of the first and second targeting domains differ in specific affinity by a factor of about 1,000 to about 10,000. 
     
     
         11 . The compound of  claim 9 , wherein the blood-protein binding domain is selected from one or more of myristic acid, a substituted or unsubstituted indole-2-carboxylic acid, a substituted or unsubstituted thioamide, a substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butanoic acid, a substituted or unsubstituted naphthalene acylsulfonamide, a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 4-iodophenylalkanoic acid, a substituted or unsubstituted 3-(4-iodophenyl)propionic acid, a substituted or unsubstituted 2-(4-iodophenyl)acetic acid, or a substituted or unsubstituted 4-(4-iodophenyl)butanoic acid. 
     
     
         12 . The compound of  claim 9 , wherein the tumor-binding domain binds to the FAP-alpha with moderate to high affinity. 
     
     
         13 . The compound of  claim 9 , wherein the imaging agent-containing domain further comprises a positron-emitting isotope. 
     
     
         14 . The compound of  claim 9 , wherein the positron-emitting isotope is  18 F or  68 Ga.