Selective high-affinity polydentate ligands and methods of making such

Patent metadata

Field	Value
Publication number	US-10646502-B2
Application number	US-201715703848-A
Country	US
Kind code	B2
Filing date	Sep 13, 2017
Priority date	Apr 21, 2008
Publication date	May 12, 2020
Grant date	May 12, 2020

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.

First claim

What is claimed is:

1. A method of inhibiting the growth or proliferation of a cancer cell that expresses an HLA-DR10 marker, said method comprising:
contacting said cancer cell with a selective high-affinity polydentate ligand (SHAL), wherein-the SHAL comprises the structure:

wherein R 1 is selected from the group consisting of COOH, a linker, an effector, and a linker attached to an effector, wherein:
when R 1 is a linker, the linker is polyethylene glycol, biotin, lysine, or a combination of polyethylene glycol and lysine; and
when R 1 is an effector, the effector is selected from:
(a) avidin, streptavidin, neutravidin, a second SHAL, biotin, a liposome, micelle, thymidine kinase; boron, uranium, or
a chelate comprising a metal isotope selected from the group consisting of 213 Bi, 212 Bi, 111 In, 64 Cu, 186 Re, 188 Re, 90 Y, 67 Cu, 169 Er, 121 Sn, 127 Te, 142 Pr, 143 Pr, 198 Au, 199 Au, 161 Tb, 109 Pd, 165 Dy, 149 Pm, 151 Pm, 153 Sm, 157 Gd, 159 Gd, 166 Ho, 172 Tm, 169 Yb, 177 Lu, 175 Yb, 105 Rh, 111 Ag, and Iodine-131;
(b) doxorubicin, biotin or a chelator selected from the group consisting of DOTA, EDTA, DTPA, CDTA, EGTA, HBED, TTHA, HEDTA, TETA, 2-2-iminothiolane, 2-iminothiacyclohexane, or 2-imino-4-mercaptomethylthiolane with bound metal isotope;
(c) a transduction peptide selected from the group consisting of oligoarginine, hexa-arginine, SV40 T antigen nuclear localization signal, the HIV Tat protein transduction domain, the integrin-binding peptide (RGD), the heparin-binding domain of vitronectin (VN peptide), antennapedia protein of Drosophila , VP22, lactosylated polylysine, poly-L-lysine, SGEHTNGPSKTSVRWVWD, SMTTMEFGHSMITPYKID, QDGGTWHLVAYCAKSHRY, MSDPNMNPGTLGSSHILW, SPGNQSTGVIGTPSFSNH, SSGANYFFNAIYDFLSNF, or GTSRANSYDNLLSETLTQ
(d) a cytotoxin or cytotoxic agent selected from the group consisting of, Diptheria toxin, Pseudomonas exotoxin A, ricin, abrin, modeccin A, alpha sacrin, Pokeweed antiviral protein S, Pokeweed antiviral protein type II, curcin, crotin, gelonin, mitogillin, restrictocin, phenomycin, and enomycin;
(e) an enzyme inhibitor selected from the group consisting of 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)acrylate, 2-(((3-chloro-5(trifluoromethyl)pyridin-2-yloxy)phenyl)methyl)acrylate, 2-(((3-chloro-5(trifluoromethyl)pyridin-2-yloxy)phenyl)methyl) acrylonitrile, 3-(3-chloro-4-{[5-(trifluoromethyl)-2-pyridinyl]oxy}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-(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-(α, α, α-trifluoro-p-tolyloxy)phenoxy]propanoic acid; or
(f) a radiosensitizer selected from the group consisting of photofrin, 1,2,4-benzotriazine-3-amino-1,4-dioxide, cisplatin, cis-dichlorodiamineplatinum, and 1,2-diamino-4-nitrobenzene)dichloroplatinum II.

2. The method of claim 1 , wherein the cancer cell expresses an epitope recognized by a Lym-1 antibody.

3. The method of claim 1 , wherein said SHAL comprises the structure:

wherein R 2 is H, COOH, or an effector;
when R 2 is an effector, the effector is selected from:

(a) avidin, streptavidin, neutravidin, a second SHAL, biotin, a liposome, micelle, thymidine kinase; boron, uranium, or
a chelate comprising a metal isotope selected from the group consisting of 213 Bi, 212 Bi, 111 In, 64 Cu, 186 Re, 188 Re, 90 Y, 67 Cu, 169 Er, 121 Sn, 127 Te, 142 Pr, 143 Pr, 198 Au, 199 Au, 161 Tb, 109 Pd, 165 Dy, 149 Pm, 151 Pm, 153 Sm, 157 Gd, 159 Gd, 166 Ho, 172 Tm, 169 Yb, 177 Lu, 175 Yb, 105 Rb, 111 Ag, and Iodine-131;
(b) doxorubicin, biotin or a chelator selected from the group consisting of DOTA, EDTA, DTPA, CDTA, EGTA, HBED, TTHA, HEDTA, TETA, 2-2-iminothiolane, 2-iminothiacyclohexane, or 2-imino-4-mercaptomethylthiolane with bound metal isotope;
(c) a transduction peptide selected from the group consisting of oligoarginine, hexa-arginine, SV40 T antigen nuclear localization signal, the HIV Tat protein transduction domain, the integrin-binding peptide (RGD), the heparin-binding domain of vitronectin (VN peptide), antennapedia protein of Drosophila , VP22, lactosylated polylysine, poly-L-lysine, SGEHTNGPSKTSVRWVWD, SMTTMEFGHSMITPYKID, QDGGTWHLVAYCAKSHRY, MSDPNMNPGTLGSSHILW, SPGNQSTGVIGTPSFSNH, SSGANYFFNAIYDFLSNF, or GTSRANSYDNLLSETLTQ
(d) a cytotoxin or cytotoxic agent selected from the group consisting of, Diptheria toxin, Pseudomonas exotoxin A, ricin, abrin,-modeccin A, alpha sacrin, Pokeweed antiviral protein S, Pokeweed antiviral protein type II, curcin, crotin, gelonin, mitogillin, restrictocin, phenomycin, and enomycin;
(e) an enzyme inhibitor selected from the group consisting of 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)acrylate, 2-(((3-chloro-5(trifluoromethyl)pyridin-2-yloxy)phenyl)methyl)acrylate, 2-(((3-chloro-5(trifluoromethyl)pyridin-2-yloxy)phenyl)methyl) acrylonitrile, 3-(3-chloro-4-{[5-(trifluoromethyl)-2-pyridinyl]oxy } 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-(6-chloro-1,3-benzoxazol-2-yloxy)phenoxy]propanoic acid, (RS)-2-[4-(2,4-dichlorophenoxy)phenoxy]propanoic acid, (RS)-2-{[5-(trifluoro methyl)-2-pyridyloxy]phenoxy }propanoic acid, (RS)-2-[4-(6-chloroquinoxalin-2-yloxy)phenoxy]propanoic acid, and (RS)-2-[4-(α, α, α-trifluoro-p-tolyloxy)phenoxy]propanoic acid; or
a radiosensitizer selected from the group consisting of photofrin, 1,2,4-benzotriazine-3-amino-1,4-dioxide, cisplatin, cis-dichlorodiamineplatinum, and 1,2-diamino-4-nitrobenzene)dichloroplatinum II.

4. A method of treating lymphoma or leukemia in a subject in need comprising orally administering to the subject a selective high-affinity polydentate ligand (SHAL) comprising the structure:

wherein R 1 is selected from the group consisting of COOH, a linker, an effector, and a linker attached to an effector, wherein:
when R 1 is a linker, the linker is polyethylene glycol, biotin, lysine, or a combination of polyethylene glycol and lysine; and
when R 1 is an effector, the effector is selected from:
(a) avidin, streptavidin, neutravidin, a second SHAL, biotin, a liposome, micelle, thymidine kinase; boron, uranium, or
a chelate comprising a metal isotope selected from the group consisting of 213 Bi, 212 Bi, 111 In, 64 Cu, 186 Re, 188 Re, 90 Y, 67 Cu, 169 Er, 121 Sn, 127 Te, 142 Pr, 143 Pr, 198 Au, 199 Au, 161 Tb, 109 Pd, 165 Dy, 149 Pm, 151 Pm, 153 Sm, 157 Gd, 159 Gd, 166 Ho, 172 Tm, 169 Yb, 177 Lu, 175 Yb, 105 Rh, 111 Ag, and Iodine-131;
(b) doxorubicin, biotin or a chelator selected from the group consisting of DOTA, EDTA, DTPA, CDTA, EGTA, HBED, TTHA, HEDTA, TETA, 2-2-iminothiolane, 2-iminothiacyclohexane, or 2-imino-4-mercaptomethylthiolane with bound metal isotope

Assignees

• L Livermore Nat Security Llc
• Univ California
• Lawrence Livermore Nat Security

Inventors

• Denardo Sally J
• Denardo Gerald L
• Balhorn Rodney L

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61K47/64

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61P35/04

  specific for metastasis · CPC title