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

Patent metadata

Field	Value
Publication number	US-10806806-B2
Application number	US-201816134789-A
Country	US
Kind code	B2
Filing date	Sep 18, 2018
Priority date	Jun 23, 2016
Publication date	Oct 20, 2020
Grant date	Oct 20, 2020

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 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 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.

2. The compound of claim 1 , 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.

3. The compound of claim 1 , 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.

4. The compound of claim 1 , 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.

5. The compound of claim 1 , wherein the tumor-binding domain binds to the PSMA with moderate to high affinity.

6. The compound of claim 1 , wherein the cytocidal or cytostatic therapeutic agent is a toxin, a venom, a metabolic poison, or a chemotherapeutic agent.

7. The compound of claim 1 , wherein the therapeutic domain comprises a covalently conjugated chelating agent or a covalently conjugated polyaza polycarboxylic macrocycle.

8. The compound of claim 7 , wherein the therapeutic domain further comprises an auger electron-emitting radionuclide, a beta-emitting radionuclide, or an alpha-emitting radionuclide.

9. The compound of claim 8 , wherein the therapeutic domain comprises 177 Lu 3+ , 175 Lu 3+ , 45 Sc 3+ , 66 Ga 3+ , 67 Ga 3+ , 68 Ga 3+ , 69 Ga 3+ , 71 Ga 3+ , 90 Y 3+ , 89 Y 3+ , 86 Y 3+ , 89 Zr 4+ , 90 Y 3+ , 99m Tc +1 , 111 In 3+ , 113 In 3+ , 115 In 3+ , 139 La 3+ , 136 Ce 3+ , 138 Ce 3+ , 140 Ce 3+ , 142 Ce 3+ , 151 Eu 3+ , 153 Eu 3+ , 152 Dy 3+ , 149 Tb 3+ , 159 Tb 3+ , 154 Gd 3+ , 155 Gd 3+ , 156 Gd 3+ , 157 Gd 3+ , 158 Gd 3+ , 160 Gd 3+ , 188 Re +1 , 186 Re +1 , 213 Bi 3+ , 227 Th 4+ , 226 Th 4+ , 225 Ac 3+ , 233 Ra 2+ , 152 Dy 3+ , 213 Bi 3+ , 212 Bi 3+ , 211 Bi 3+ , 212 Pb 2+ , 212 Pb 4+ , 255 Fm 3+ , or uranium-230.

10. The compound of claim 8 , wherein the therapeutic domain comprises 213 Bi 3+ , 211 At + , 225 Ac 3+ , 152 Dy 3+ , 212 Bi 3+ , 211 Bi 3+ , 217 At + , 227 Th 4+ , 226 Th 4+ , 233 Ra 2+ , 212 Pb 2+ , or 212 Pb 4+ .

11. The compound of claim 8 , wherein the therapeutic domain comprises 177 Lu 3+ , 90 Y 3+ , 188 Re +1 , or 186 Re +1 .

12. The compound of claim 8 , wherein the compound is (((S)-1-carboxy-5-(3-(3-(1-((14S,45S)-45-carboxy-14-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-54-(4-iodophenyl)-12,15,43,51-tetraoxo-3,6,9,19,22,25,28,31,34,37,40-undecaoxa-13,16,44,50-tetraazatetrapentacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid chelating 225 Ac 3+ .

13. The compound of claim 8 , wherein the compound is (((S)-1-carboxy-5-(3-(3-(1-((14S,45S)-45-carboxy-14-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-54-(4-iodophenyl)-12,15,43,51-tetraoxo-3,6,9,19,22,25,28,31,34,37,40-undecaoxa-13,16,44,50-tetraazatetrapentacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid chelating 233 Ra 2+ .

14. The compound of claim 8 , wherein the compound is (((S)-1-carboxy-5-(3-(3-(1-((14S,45S)-45-carboxy-14-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-54-(4-iodophenyl)-12,15,43,51-tetraoxo-3,6,9,19,22,25,28,31,34,37,40-undecaoxa-13,16,44,50-tetraazatetrapentacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid chelating 213 Bi 3+ .

15. The compound of claim 8 , wherein the compound is (((S)-1-carboxy-5-(3-(3-(1-((14S,45S)-45-carboxy-14-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-54-(4-iodophenyl)-12,15,43,51-tetraoxo-3,6,9,19,22,25,28,31,34,37,40-undecaoxa-13,16,44,50-tetraazatetrapentacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid chelating 212 Pb 2+ or 212 Pb 4+ .

Assignees

• Univ Cornell

Inventors

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

Classifications

• 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

• A61K51/0482 Primary

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

• A61P35/00

  Antineoplastic agents · CPC title