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US 10,292,992 B2Granted
Selective high-affinity polydentate ligands and methods of making such
AssigneesLawrence Livermore National Security, LLC, The Regents of the University of California
InventorsSally J. DeNardo, Gerald L. DeNardo, Rodney L. Balhorn
Life of this patent
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Abstract
This invention provides novel polydentate selective high affinity ligands (SHALs) that can be used in a variety of applications in a manner analogous to the use of antibodies. SHALs typically comprise a multiplicity of ligands that each bind different region son the target molecule. The ligands are joined directly or through a linker thereby forming a polydentate moiety that typically binds the target molecule with high selectivity and avidity.
Claims25
A method of detecting a cancer cell, said method comprising:
- contacting said cancer cell with a chimeric molecule comprising a selective high affinity ligand (SHAL) that specifically binds to the cancer cell, the SHAL attached to a detectable label, and detecting the presence or absence of said detectable label, wherein said SHAL has the structure:
- wherein R1 is selected from the group consisting of COOH, a linker, an effector, and a linker attached to an effector wherein:
- when R1 is a linker, the linker is selected from avidin, biotin, polyethylene glycol (PEG), or PEG and a lysine;
- and
- when R1 is an effector, the effector is selected from avidin, biotin, and a cytotoxin selected from the group of a Diphtheria toxin, a Pseudomonas exotoxin, a ricin, an abrin, and a thymidine kinase, a chelate comprising (a) a metal isotope selected from the group of 99Tc, 203Pb, 67Ga, 68Ga, 72As, 111In, 113mIn, 97Ru, 62Cu, 64lcu, 52Fe, 52mMn, 51Cr, 186, Re, 188Re, 77As, 90Y, 67Cu, 169Er, 121Sn, 127Te, 142Pr, 143Pr, 198Au, 199Au, 161Tb, 109Pd, 165Dy, 149Pm, 151Pm, 153Sm, 157Gd, 159Gd, 166Ho, 172Tm, 169Yb, 175Yb, 177Lu, 105Rh, and 111Ag, (b) bismuth 213, or (c) DOTA, 4[[5-(Trifluoromethyl)pyridin-2-yl]oxy]phenyl]N-phenylcarbamate, (R)-2-[4-(5-chloro-3-fluoro-2-pyridyloxy)phenoxy]propionic acid, 2-(((3-chloro-5 (trifluoromethyl)pyridin-2-yloxy)phenoxy)methyl)acrylates, 2-(((3-chloro-5 (trifluoromethyl)pyridin-2-yloxy)phenyl)methyl)acrylates, 2-(((3-chloro-5 (trifluoromethyl)pyridin-2-yloxy)phenyl)methyl)acrylonitriles, 3-(3-chloro-4-{[5-(trifluoromethyl)-2-pyridinylloxy}anilino)-3-oxopropanoic acid, Sethoxydim, Clethodim, 5-(Tetradecyloxy)-2-furoic acid, 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid, 2-[4-(4-Chlorophenoxy)phenoxy]propanoic acid, (RS)-2-{4-[3-chloro-5-(trifluoromethyl)-2-pyridinylloxy]phenoxy}propanoic acid, (RS)-2-[4-(6-chloro-1,3-benzoxazol-2-yloxy)phenoxy]propanoic acid, (RS)-2-[4-(2,4-dichlorophenoxy)phenoxy]propanoic acid, (RS)-2-{4-[5-(trifluoromethyl)-2-pyridyloxy]phenoxy}propanoic acid, (RS)-2-[4-(6-chloroquinoxalin-2-yloxy)phenoxy]propanoic acid, and (RS)-2-[4-(a, a, a-trifluoro-p-tolyloxy)phenoxy]propanoic acid.
2 more elements
A method of detecting cancer in a subject, said method comprising:
- contacting a sample isolated from the subject with a chimeric molecule comprising a selective high affinity ligand (SHAL) that specifically binds to a cancer cell, the SHAL attached to detectable label, wherein said SHAL has the structure:
- wherein R1 is selected from the group consisting of COOH, a linker, an effector, and a linker attached to an effector wherein:
- when R1 is a linker, the linker is selected from avidin, biotin, polyethylene glycol (PEG), or PEG and a lysine;
- and
- when R1 is an effector, the effector is selected from avidin, biotin, and a cytotoxin selected from the group of a Diphtheria toxin, a Pseudomonas exotoxin, a ricin, an abrin, and a thymidine kinase, a chelate comprising (a) a metal isotope selected from the group of 99Tc, 203Pb, 67Ga, 68Ga, 72As, 111In, 113mIn, 97Ru, 62Cu, 64lcu, 52Fe, 52mMn, 51Cr, 186, Re, 188Re, 77As, 90Y, 67Cu, 169Er, 121Sn, 127Te, 142Pr, 143Pr, 198Au, 199Au, 161Tb, 109Pd, 165Dy, 149Pm, 151Pm, 153Sm, 157Gd, 159Gd, 166Ho, 172Tm, 169Yb, 175Yb, 177Lu, 105Rh, and 111Ag, (b) bismuth 213, or (c) DOTA, 4[[5-(Trifluoromethyl)pyridin-2-yl]oxy]phenyl]N-phenylcarbamate, (R)-2-[4-(5-chloro-3-fluoro-2-pyridyloxy)phenoxy]propionic acid, 2-(((3-chloro-5 (trifluoromethyl)pyridin-2-yloxy)phenoxy)methyl)acrylates, 2(((3-chloro-5(trifluoromethyl)pyridin-2-yloxy)phenyl)methyl)acrylates, 2-(((3-chloro-5 (trifluoromethyl)pyridin-2-yloxy)phenyl)methyl)acrylonitriles, 3-(3-chloro-44[5-(trifluoromethyl)-2-pyridinylloxy}anilino)-3-oxopropanoic acid, Sethoxydim, Clethodim, 5-(Tetradecyloxy)-2-furoic acid, 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid, 2-[4-(4-Chlorophenoxy)phenoxy]propanoic acid, (RS)-2-{4-[3-chloro-5-(trifluoromethyl)-2-pyridinylloxy]phenoxy}propanoic acid, (RS)-2-[4-(6-chloro-1,3-benzoxazol-2-yloxy)phenoxy]propanoic acid, (RS)-2-[4-(2,4-dichlorophenoxy)phenoxy]propanoic acid, (RS)-2-{4-[5-(trifluoromethyl)-2-pyridyloxy]phenoxy}propanoic acid, (RS)-2-[4-(6-chloroquinoxalin-2-yloxy)phenoxy]propanoic acid, and (RS)-2-[4-(a, a, a-trifluoro-p-tolyloxy)phenoxy]propanoicacid;
- and
- detecting a cancer cell bound to the labeled SHAL, thereby detecting cancer.
4 more elements
Dependencies are inferred from the claim text.