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

Patent metadata

Field	Value
Publication number	US-2019015531-A1
Application number	US-201816134789-A
Country	US
Kind code	A1
Filing date	Sep 18, 2018
Priority date	Jun 23, 2016
Publication date	Jan 17, 2019
Grant date	—

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.

First claim

What is claimed is:

1 . A compound comprising: a tumor-binding domain, an albumin-binding domain, and a cytocidal or cytostatic therapeutic agent, wherein the tumor-binding domain comprises an active site that is distal to and sterically unimpeded by the albumin-binding domain and the therapeutic agent, 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 (av(33), 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 the tumor-binding domain binds to the tumor associated molecular target with moderate to high affinity.

4 . The compound of claim 1 , wherein the cytocidal or cytostatic therapeutic agent is a toxin, a venom, a metabolic poison, a chemotherapeutic agent, an auger electron-emitting radionuclide, a beta-emitting radionuclide, or an alpha-emitting radionuclide.

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 a therapeutic domain comprising a cytocidal or cytostatic therapeutic agent.

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 (av(33), 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 cytocidal or cytostatic therapeutic agent is a toxin, a venom, a metabolic poison, a chemotherapeutic agent, an auger electron-emitting radionuclide, a beta-emitting radionuclide, or an alpha-emitting radionuclide.

9 . The compound of claim 5 , wherein the therapeutic domain comprises a covalently conjugated chelating agent or a covalently conjugated polyaza polycarboxylic macrocycle.

10 . The compound of claim 9 , wherein the therapeutic domain further comprises an auger electron-emitting radionuclide, a beta-emitting radionuclide, or an alpha-emitting radionuclide.

11 . 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 PSMA 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 a therapeutic domain comprising a cytocidal or cytostatic therapeutic agent.

12 . The compound of claim 11 , 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 PSMA 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.

13 . The compound of claim 11 , wherein the tumor-binding domain comprises a glutamate-ureido-amino acid sequence, a glutamate-urea-lysine sequence optionally with a substituted or unsubstituted aryl group or a substituted or unsubstituted arylene group at the epsilon amine of lysine, or a derivative thereof that occludes the PSMA receptor active site.

14 . The compound of claim 11 , 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.

15 . The compound of claim 11 , wherein the tumor-binding domain binds to the PSMA with moderate to high affinity.

16 . The compound of claim 11 , wherein the cytocidal or cytostatic therapeutic agent is a toxin, a venom, a metabolic poison, a chemotherapeutic agent, an auger electron-emitting radionuclide, a beta-emitting radionuclide, or an alpha-emitting radionuclide.

17 . The compound of claim 11 , wherein the therapeutic domain comprises a covalently conjugated chelating agent or a covalently conjugated polyaza polycarboxylic macrocycle.

18 . The compound of claim 17 , wherein the therapeutic domain further comprises an auger electron-emitting radionuclide, a beta-emitting radionuclide, or an alpha-emitting radionuclide.

Assignees

• Univ Cornell

Inventors

• Babich John W
• Kelly James M
• Amor-Coarasa Alejandro
• Ponnala Shashikanth

Classifications

• A61K51/0482 Primary

  chelates from cyclic ligands, e.g. DOTA · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0497

  conjugates with a carrier being an organic compounds · CPC title

• A61K51/0402

  carboxylic acid carriers, fatty acids (amino acids A61K51/0406) · CPC title