Granted Patent
B2
US 12,246,015 · App. 16/967,283 · Granted Mar 11, 2025
Alpha polyglutamated raltitrexed and uses thereof
Assignee:
L.E.A.F. HOLDINGS GROUP LLC
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The disclosure relates generally to alpha polyglutamated raltitrexed, formulations containing liposomes filled with alpha polyglutamated raltitrexed, methods of making the alpha polyglutamated raltitrexed and liposome containing formulations, and methods of using polyglutamated alpha polyglutamated raltitrexed and liposome containing formulations to treat hyperproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., an autoimmune disease such as rheumatoid arthritis).
Claims (44)
1. A liposomal composition comprising a liposome encapsulating an alpha polyglutamated raltitrexed, wherein the polyglutamated raltitrexed comprises 2-10 glutamyl groups having alpha carboxyl group linkages, and wherein the liposome does not contain a targeting moiety having specific affinity for a surface antigen on a target cell.
2. The liposomal composition of claim 1 , wherein the alpha polyglutamated raltitrexed comprises 4-6 glutamyl groups having alpha carboxyl group linkages.
3. The liposomal composition of claim 1 , wherein the alpha polyglutamated raltitrexed contains 4, 5, or 6, glutamyl groups having alpha carboxyl group linkages.
4. The liposomal composition of claim 1 , wherein:
(a) three glutamyl groups of the polyglutamated raltitrexed have an alpha carboxyl group linkage;
(b) each of the glutamyl groups of the polyglutamated raltitrexed other than the glutamyl group of raltitrexed has an alpha carboxyl group linkage;
(c) each of the glutamyl groups of the polyglutamated raltitrexed other than the C-terminal glutamyl group or groups and the glutamyl group of raltitrexed has an alpha carboxyl group linkage;
(d) each of the glutamyl groups of the polyglutamated raltitrexed other than the C-terminal glutamyl group or groups has an alpha carboxyl group linkage; or
(e) at least one glutamyl group of the polyglutamated raltitrexed has both an alpha carboxyl group linkage and a gamma carboxyl group linkage.
5. The liposomal composition of claim 1 , wherein:
(a) at least 2 of the glutamyl groups of the alpha polyglutamated are in the L-form,
(b) each of the glutamyl groups of the alpha polyglutamated raltitrexed is in the L-form,
(c) at least 1 of the glutamyl groups of the alpha polyglutamated raltitrexed is in the D-form,
(d) each of the glutamyl groups of the alpha polyglutamated raltitrexed other than the glutamyl group of raltitrexed is in the D-form, or
(e) at least 2 of the glutamyl groups of the alpha polyglutamated raltitrexed are in the L-form and at least 1 of the glutamyl groups is in the D-form.
6. The liposomal composition of claim 1 , wherein the liposome comprises an alpha tetraglutamated raltitrexed.
7. The liposomal composition of claim 1 , wherein the liposome comprises an alpha pentaglutamated raltitrexed.
8. The liposomal composition of claim 1 , wherein the liposome comprises an alpha hexaglutamated raltitrexed.
9. The liposomal composition of claim 1 , wherein the polyglutamate is linear or branched.
10. The liposomal composition of claim 1 , wherein the liposome is pegylated.
11. The liposomal composition of claim 1 , wherein the liposome is not pegylated.
12. The liposomal composition of claim 1 , wherein the liposome has a diameter in the range of 20 nm to 500 nm, 20 nm to 200 nm, or 80 nm to 120 nm.
13. The liposomal composition of claim 1 , wherein the liposome is formed from liposomal components comprising:
at least one of an anionic lipid and a neutral lipid;
at least one selected from: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE); DSPE-PEG; DSPE-PEG-maleimide; hydrogenated soy phosphatidylcholine (HSPC); HSPC-PEG; cholesterol; cholesterol-PEG; and cholesterol-maleimide; or
at least one selected from: DSPE; DSPE-PEG; DSPE-PEG-FITC; DSPE-PEG-maleimide; cholesterol; and HSPC.
14. The liposomal composition of claim 13 , wherein one or more liposomal components further comprises at least one steric stabilizer selected from: polyethylene glycol (PEG); poly-L-lysine (PLL); monosialoganglioside (GM1); poly(vinyl pyrrolidone) (PVP); poly(acrylamide) (PAA); poly(2-methyl-2-oxazoline); poly(2-ethyl-2-oxazoline); phosphatidyl polyglycerol; poly[N-(2-hydroxypropyl) methacrylamide]; amphiphilic poly-N-vinylpyrrolidones; L amino-acid-based polymer; oligoglycerol, copolymer containing polyethylene glycol and polypropylene oxide, Poloxamer 188, and polyvinyl alcohol.
15. The liposomal composition of claim 14 , wherein the steric stabilizer is PEG and the PEG has a number average molecular weight (Mn) of 200 to 5000 daltons.
16. The liposomal composition of claim 1 , wherein the liposome is anionic or neutral.
17. The liposomal composition of claim 1 , wherein the liposome has a zeta potential that is less than or equal to zero, between 0 to −150 mV, or between −30 to −50 mV.
18. The liposomal composition of claim 1 , wherein the liposome is cationic.
19. The liposomal composition of claim 1 , wherein the liposome has an interior space comprising the alpha polyglutamated raltitrexed and an aqueous pharmaceutically acceptable carrier comprising:
a tonicity agent at a concentration of greater than 1% w/v;
1% to 50% w/v trehalose;
1% to 50% w/v dextrose;
5% w/v dextrose suspended in an HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffered solution; or
a total concentration of sodium acetate and calcium acetate of between 50 mM to 500 mM.
20. The liposomal composition of claim 19 , wherein the interior space of the liposome has a pH of 5-8 or a pH of 6-7.
21. The liposomal composition of claim 1 , wherein the liposome comprises less than 500,000, less than 200,000, or between 10 to 100,000 molecules of the alpha polyglutamated raltitrexed.
22. The liposomal composition of claim 10 , further comprising one or more of an immunostimulatory agent, a detectable marker and a maleimide, wherein the immunostimulatory agent, the detectable marker or the maleimide is attached to said PEG or the exterior of the liposome.
23. The liposomal composition of claim 22 , wherein the immunostimulatory agent is at least one selected from: a fluorescein; a fluorescein isothiocyanate (FITC); a dinitrophenol (DNP); a beta glucan; a beta-1,3-glucan; a beta-1,6-glucan; a resolvin; and a Toll-like receptor (TLR) modulating agent.
24. The liposomal composition of claim 1 , which further comprises at least one cryoprotectant selected from mannitol, trehalose, sorbitol, and sucrose.
25. The liposomal composition of claim 1 , which further comprises carboplatin and/or pembrolizumab.
26. A pharmaceutical composition comprising the liposomal composition of claim 1 .
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 23, 2021
From: NIYIKIZA, CLET; MOYO, VICTOR MANDLA
To: L.E.A.F. HOLDINGS GROUP LLC
Reel/Frame 055374/0824 →
Continuity (6)
Provisional Application
62702732
· Jul 24, 2018
Provisional Application
62764943
· Aug 17, 2018
Provisional Application
62630671
· Feb 14, 2018
Provisional Application
62627741
· Feb 7, 2018
Provisional Application
62662374
· Apr 25, 2018
References Cited (232)
US 4584375A
· Coward
· 1986
[cited by applicant]
US 5268362A
· Akimoto et al.
· 1993
[cited by applicant]
US 5912251A
· Nair
· 1999
[cited by applicant]
US 6569432B1
· Israeli et al.
· 2003
[cited by applicant]
US 7053065B2
· Niyikiza et al.
· 2006
[cited by applicant]
US 7399461B2
· Heston et al.
· 2008
[cited by applicant]
US 7446120B2
· Gour et al.
· 2008
[cited by applicant]
US 7772209B2
· Niyikiza
· 2010
[cited by applicant]
US 8466111B2
· Jansen et al.
· 2013
[cited by applicant]
US 8747869B2
· Irvine et al.
· 2014
[cited by applicant]
US 9207238B2
· Ando et al.
· 2015
[cited by applicant]
US 9261509B2
· Dervieux
· 2016
[cited by applicant]
US 9440979B2
· Lahiri et al.
· 2016
[cited by applicant]
US 20010046533A1
· Bailey et al.
· 2001
[cited by applicant]
US 20040001846A1
· Israeli et al.
· 2004
[cited by applicant]
US 20050031679A1
· Unger et al.
· 2005
[cited by applicant]
US 20050163832A1
· Torchilin
· 2005
[cited by applicant]
US 20060063768A1
· Mueller et al.
· 2006
[cited by applicant]
US 20070270431A1
· Tabunoki et al.
· 2007
[cited by applicant]
US 20080260812A1
· Matsuyama et al.
· 2008
[cited by applicant]
US 20090155345A1
· Barenholz et al.
· 2009
[cited by applicant]
US 20090234298A1
· Habeshaw et al.
· 2009
[cited by applicant]
US 20100203539A1
· Dervieux
· 2010
[cited by applicant]
US 20100266709A1
· Hicks
· 2010
[cited by applicant]
US 20120258450A1
· Norfray
· 2012
[cited by applicant]
US 20130122096A1
· Shemi et al.
· 2013
[cited by applicant]
US 20130165654A1
· Kadaboina et al.
· 2013
[cited by applicant]
US 20140086939A1
· Karin et al.
· 2014
[cited by applicant]
US 20140120157A1
· Chang et al.
· 2014
[cited by applicant]
US 20150239956A1
· Koguma et al.
· 2015
[cited by applicant]
US 20160228573A1
· Niyikiza et al.
· 2016
[cited by applicant]
US 20180236098A1
· Niyikiza et al.
· 2018
[cited by applicant]
US 20210220494A1
· Bradbury et al.
· 2021
[cited by applicant]
US 20220279831A1
· Perrin et al.
· 2022
[cited by applicant]
CN 103040748A
· 2013
[cited by applicant]
RU 2423114C2
· 2011
[cited by applicant]
WO WO2001005405A1
· 2001
[cited by applicant]
WO WO200195884A2
· 2001
[cited by applicant]
WO WO2004087115A2
· 2004
[cited by applicant]
WO WO2005070465A2
· 2005
[cited by applicant]
WO WO2005089767A1
· 2005
[cited by applicant]
WO WO2011106528A2
· 2005
[cited by applicant]
WO WO2006002049A2
· 2006
[cited by applicant]
WO WO2006029385A2
· 2006
[cited by applicant]
WO WO2006074416A1
· 2006
[cited by applicant]
WO WO2007023243A2
· 2007
[cited by applicant]
WO WO2007098089A2
· 2007
[cited by applicant]
WO WO2008030818A2
· 2008
[cited by applicant]
WO WO2009153575A1
· 2009
[cited by applicant]
WO WO2011143484A1
· 2011
[cited by applicant]
WO WO2011150392A1
· 2011
[cited by applicant]
WO WO2012061469A2
· 2012
[cited by applicant]
WO WO2012061759A2
· 2012
[cited by applicant]
WO WO2012118806A2
· 2012
[cited by applicant]
WO WO2013008240A2
· 2013
[cited by applicant]
WO WO2013012722A1
· 2013
[cited by applicant]
WO WO2014046630A1
· 2014
[cited by applicant]
WO WO2014186403A2
· 2014
[cited by applicant]
WO 2016025882A1
· 2016
[cited by examiner]
WO WO2017123517A1
· 2017
[cited by applicant]
WO WO2018031967A1
· 2018
[cited by applicant]
WO WO2018031968A1
· 2018
[cited by applicant]
WO WO2018031979A1
· 2018
[cited by applicant]
WO WO2018031980A1
· 2018
[cited by applicant]
WO WO2019094648A1
· 2019
[cited by applicant]
WO WO2019157120A1
· 2019
[cited by applicant]
WO WO2019157121A1
· 2019
[cited by applicant]
WO WO2019157123A1
· 2019
[cited by applicant]
WO WO2019157125A1
· 2019
[cited by applicant]
WO WO2019157129A1
· 2019
[cited by applicant]
WO WO2019157133A1
· 2019
[cited by applicant]
WO WO2019157138A1
· 2019
[cited by applicant]
WO WO2019157140A1
· 2019
[cited by applicant]
WO WO2019157145A1
· 2019
[cited by applicant]
WO WO2019157146A1
· 2019
[cited by applicant]
WO WO2019157148A1
· 2019
[cited by applicant]
WO WO2019160732A1
· 2019
[cited by applicant]
WO WO2019160733A1
· 2019
[cited by applicant]
WO WO2019160734A1
· 2019
[cited by applicant]
WO WO2019160735A1
· 2019
[cited by applicant]
WO WO2019160736A1
· 2019
[cited by applicant]
WO WO2021026310A1
· 2021
[cited by applicant]
International Search Report for PCT/US2019/016978 dated Apr. 26, 2019, 4 pages.
[cited by applicant]
Written Opinion of the ISA for PCT/US2019/016978 dated Apr. 26, 2019, 5 pages.
[cited by applicant]
International Search Report for PCT/US2019/016955, mailed Apr. 24, 2019, 4 pages.
[cited by applicant]
Written Opinion of the ISA for PCT/US2019/016955, mailed Apr. 24, 2019, 5 pages.
[cited by applicant]
Assaraf, Y. G., et al., “Characterization of the Coexisting Multiple Mechanisms of Methotrexate Resistance in Mouse 3T6 R50 Fibroblasts.” J. Biological Chemistry, 267(9):5776-5784 (1992).
[cited by applicant]
Banerjee, D., et al., “Molecular mechanisms of resistance to antifolates, a review.” Acta Biochim Pol., 42(4):457-464 (1995).
[cited by applicant]
Bertino, J. R., et al., “Resistance Mechanisms to Methotrexate in Tumors.” Stem Cells, 14:5-9 (1996).
[cited by applicant]
Bozzuto, G., et al., “Liposomes as nanomedical devices,” Intl. J. Nanomed. 10:975-999 (2015).
[cited by applicant]
Bulbake, U., et al., “Liposomal Formulations in Clinical Use: An Updated Review.” Pharmaceutics, 9(12):1-33 (2017).
[cited by applicant]
Chabner, B. A., et al., “Polyglutamation of Methotrexate Is Methotrexate a Prodrug?” Journal of Clinical Investigation, 76:907-912 (1985).
[cited by applicant]
Chazal, M., et al., “Decreased Folylpolyglutamate Synthetase Activity in Tumors Resistant to Fluorouracil-Folinic Acid Treatment: Clinical Data.” Clinical Cancer Research, 3:553-557 (1997).
[cited by applicant]
Danenberg, P. V., et al., “Folates as adjuvants to anticancer agents: Chemical rationale and mechanism of action.” Crit Rev. Oncol. Hematol., 106:118-131. (2016).
[cited by applicant]
Delfino, R. T., et al., “Type 2 Antifolates in the Chemotherapy of falciparum Malaria.” J. Braz. Chem. Soc., 13(6):727-741 (2002).
[cited by applicant]
Deshpande, P., et al., “Current trends in the use of liposomes for tumor targeting.” Nanomedicine (Lond), 8(9):1-32 (2013).
[cited by applicant]
Desmoulin, S. K., et al., “The human proton-coupled folate transporter.” Cancer Biology & Therapy, 13(14):1355-1373; (2012).
[cited by applicant]
Faessel, H. M., et al., “Super in Vitro Synergy between Inhibitors of Dihydrofolate Reductase and Inhibitors of Other Folate-requiring Enzymes: The Critical Role of Polyglutamylation.” Cancer Research, 58:3036-3050 (199…
[cited by applicant]
Fan, Y., et al., “Development of liposomal formulations: From concept to clinical investigations.” Asian Journal of Pharmaceutical Sciences, 8(2):81-87 (2013).
[cited by applicant]
Fouladi, F., et al., “Enzyme-Responsive Liposomes for the Delivery of Anticancer Drug.” Bioconjug Chem., 19:28(4): 857-868 (2017).
[cited by applicant]
Galivan, J., et al., “y-Fluoromethotrexate: Synthesis and biological activity of a potent inhibitor of dihydrofolate reductase with greatly diminished ability to form poly-y-glutamates.” Proc. Natl. Acad. Sci. USA, (82)…
[cited by applicant]
Gonen, N., et al., “Antifolates in cancer therapy: Structure, activity and mechanisms of drug resistance.” Drug Resistance Updates, 15:183-210 (2012).
[cited by applicant]
Habeck L. L., et al., “A Novel Class of Monoglutamated Antifolates Exhibits Tight-binding Inhibition of Human Glycinamide Ribonucleotide Formyltransferase and Potent Activity against Solid Tumors.” Cancer Research, 54: …
[cited by applicant]
Jackman, A. L., et al., “Folate-based thymidylate synthase inhibitors as anticancer drugs.” Annals of Oncology, 6: 871-881 (1995).
[cited by applicant]
Jansen, G., et al., “Folates in rheumatoid arthritis.” Pteridines, 24(1): 21-26 (2013).
[cited by applicant]
Kim, S., et al., “Gamma-glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate.” British Journal of Cancer, 109:2175-2188 (2013).
[cited by applicant]
Kremer, J.M. “Toward a Better Understanding of Methotrexate.” Arthritis & Rheumatism, 50:1370-1382 (2004).
[cited by applicant]
Kuehl, M., et al., “Cytotoxicity, Uptake, Polyglutamate Formation, and Antileukemic Effects of 8-Deaza Analogues of Methotrexate and Aminopterin in Mice.” Cancer Research, 48:1481-1488 (1988).
[cited by applicant]
Ledermann, J. A., et al., “Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments.” Annals of Oncology, 26:2034-2043 (2015).
[cited by applicant]
Li, J., et al., “A review on phospholipids and their main applications in drug delivery systems.” Asian Journal of Pharmaceutical Science, 10(2):81-98 (2015).
[cited by applicant]
Lila, A. S., et al., “Liposomal Delivery Systems: Design Optimization and Current Applications.” Biol. Pharm. Bull., 40:1-10 (2017).
[cited by applicant]
Matherly, L. H., et al., “The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer.” Drug Metabolism and Disposition, 42:632-649 (2014…
[cited by applicant]
McCloskey, D. E., et al.,. “Decreased Folylpolyglutamate Synthetase Activity as a Mechanism of Methotrexate Resistance in CCRF-CEM Human Leukemia Sublines.” J. Biological Chemistry, 266(10):6181-6187 (1991).
[cited by applicant]
Muhale, F., et al., “Systems pharmacology assessment of the 5-fluorouracil pathway.” Pharmacogenomics, 12(3): 341-350 (2011).
[cited by applicant]
Obeid, R., et al., “Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?” J. Perinat. Med., 41(5): 469-483 (2013).
[cited by applicant]
Pavlova, N. N., et al., “The Emerging Hallmarks of Cancer Metabolism.” Cell Metab., 12;23(1):27-47 (2016).
[cited by applicant]
Reeve, S. M., et al., “Charged Propargyl-Linked Antifolates Reveal Mechanisms of Antifolate Resistance and Inhibit Trimethoprim-Resistant MRSA Strains Possessing Clinically Relevant Mutations.” J. Med. Chem., 59:6493-65…
[cited by applicant]
Rhee, M. S., et al., “Acquisition of Resistance to Antifolates Caused by Enhanced y-Glutamyl Hydrolase Activity.” Cancer Research, 53: 2227-2230 (1993).
[cited by applicant]
Rots, M. G., et al., “Role of Folylpolyglutamate Synthetase and Folylpolyglutamate Hydrolase in Methotrexate Accumulation and Polyglutamylation in Childhood Leukemia.” Blood, 93(5):1677-1683 (1999).
[cited by applicant]
Samuels, L.S., et al., “Similar Differential for Total Polyglutamylation and Cytotoxicity among Various Folate Analogues in Human and Murine Tumor Cells in Vitro.” Cancer Research, 45:1488-1495 (1985).
[cited by applicant]
Ser, A., et al., “Targeting One Carbon Metabolism with an Antimetabolite Disrupts Pyrimidine Homeostasis and Induces Nucleotide Overflow.” Cell Reports, 15(11): P2367-2376 (2016).
[cited by applicant]
Shih, C., et al., “LY231514, a Pyrrolo[2,3-d]pyrimidine-based Antifolate That Inhibits Multiple Folate-requiring Enzymes.” Cancer Research, 57:1116-1123 (1997).
[cited by applicant]
Shimamoto, Y., et al., “Association between mRNA expression of chemotherapy-related genes and clinicopathological features in colorectal cancer: A large-scale population analysis.” International Journal of Molecular Med…
[cited by applicant]
Shrestha, H., et al., “Lipid-Based Drug Delivery Systems.” Journal of Pharmaceutics, 1-10 (2014).
[cited by applicant]
Stathopoulos, G. P., et al., “Lipoplatin Formulation Review Article.” Journal of Drug Delivery, 1-10 (2012).
[cited by applicant]
Torchilin, V, P., “Recent Advances with Liposomes as Pharmaceutical Carriers.” Nature Reviews Drug Discovery, 4:145-160 (2005).
[cited by applicant]
Tsukioka, S., et al., “In vivo evidence for a significant role of folylpolyglutamate synthase in combined chemotherapy with oral fluoropyrimidine, UFT or S-1, and leucovorin.” Oncology Reports 25:1407-1412 (2011).
[cited by applicant]
Van Triest, B., et al., “Thymidylate Synthase Level as the Main Predictive Parameter for Sensitivity to 5-Fluorouracil, but not for Folate-based Thymidylate Synthase Inhibitors, in 13 Nonselected Colon Cancer Cell Lines…
[cited by applicant]
Verma, M. S., “1,3-Beta-Glucans: Drug Delivery and Pharmacology.” The Complex WO-rld of Polysaccharides, Chapter 21:551-572 (2012).
[cited by applicant]
Visentin, M., et al., “The Antifolates.” Hematol. Oncol. Clin. North Am., 26(3): 629-ix (2012).
[cited by applicant]
Wagner, A. and Vorauer-Uhl, K., “Liposome Technology for Industrial Purposes,” Journal of Drug Delivery, vol. 2011, Article ID 591325, 9 pages (2011).
[cited by applicant]
Whitehead, V. M., et al., “Accumulation of Methotrexate and Methotrexate Polyglutamates in Lymphoblasts at Diagnosis of Childhood Acute Lymphoblastic Leukemia: A Pilot Prognostic Factor Analysis.” Blood, 76(1):44-49 (19…
[cited by applicant]
Wilson, M. R., et al., “Targeting Nonsquamous Non small Cell Lung Cancer via the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo [2,3-d]Pyrimidine Thienoyl Antifolates.” Mol. Pharmacol., 89:425-434 (2016).
[cited by applicant]
Wojtuszkiewicz, A., et al., ““Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia.”” J Hematol Oncol., 8:61 (2015).
[cited by applicant]
Molina, et al., “The role of Pemetrexed in Lung Cancer Therapy”, Clinical Lung Cancer 5:21 (2003).
[cited by applicant]
Tomsho, et al., “Concentration-dependent processivity of multiple glutamate ligations catalyzed by foly-poly-gamma-glutamate synthetase” Biochemistry 47(34):9040 (2008).
[cited by applicant]
Tomsho et al., “Synthesis of (6R)- and (6S)-5,10-dideazatetrahydrofolate oligo-γ-glutamates: Kinetics of multiple glutamate ligations catalyzed by folylpoly-γ-glutamate synthetase” Org. Biomol. Chem. 3(18):3388-98 (2005…
[cited by applicant]
Besson et al., “Effects of tetrahydrofolate polyglutamates on the kinetic parameters of serine hydroxymethyltransferase and glycine decarboxylase from pea leaf mitochondria” Biochem J. (Pt 2)(Pt 2):425 (1993).
[cited by applicant]
Tsushima et al., “Fluorine containing amino acids and their derivatives. 7. Synthesis and antitumor activity of α- and γ-substituted methotrexate analogs” Tetrahedron 44(77):5375 (1988).
[cited by applicant]
Duch et al., “Biochemical and Cellular Pharmacology of 1843U89, a Novel Benzoquinazoline Inhibitor of Thymidylate Synthase” Cancer Research 53:810-818 (1993).
[cited by applicant]
Matherly et al., “Enhanced Polyglutamylation of Aminopterin Relative to Methotrexate in the Ehrlich Ascites Tumor Cell in Vitro” Cancer Research 45:1073 (1985).
[cited by applicant]
Fry et al., “Rapid formation of poly-y-glutamyl derivatives of methotrexate and their association with dihydrofolate reductase as assessed by high pressure liquid chromatography in the Ehrlich ascites tumor cell in vitr…
[cited by applicant]
National Center for Biotechnology Information (2020). PubChem Compound Summary for CID 101607589. Retrieved Nov. 22, 2020 from https://pubchem.ncbi.nlm.nih.gov/compound/101607589.
[cited by applicant]
National Center for Biotechnology Information (2020). PubChem Compound Summary for CID 267606. Retrieved Nov. 22, 2020 from https://pubchem.ncbi.nlm.nih.gov/compound/101607589.
[cited by applicant]
National Center for Biotechnology Information (2020). PubChem Compound Summary for CID 102483590. Retrieved Nov. 22, 2020 from https://pubchem.ncbi.nlm.nih.gov/compound/101607589.
[cited by applicant]
Zwicke et al., “Utilizing the folate receptor for active targeting of cancer nanotherapeutics” Nano Reviews 3(1):18496 (2012).
[cited by applicant]
Springer et al. “Prodrugs of thymidylate synthase inhibitors potential for antibody directed enzyme prodrug therapy (ADEPT)”, Anti-Cancer Drug Design, Oxford University Press, Basingstoke 11(8):625-636 (1996).
[cited by applicant]
Anonymous, “Antifolate—Wikipedia” (Dec. 29, 2020), pp. 1-5, Retrieved from the Internet: URL:https://en.wikipedia.org/wiki/ Antifolate [retrieved on Mar. 29, 2021].
[cited by applicant]
Abolmaali et al., A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis Cancer Chemotherapy and Pharmacology 71:1115-1130 (2013).
[cited by applicant]
Jackman et al., “ICI D1694, a Quinazoline Antifolate Thymidylate Synthase Inhibitor That Is a Potent Inhibitor of L1210 Tumor Cell Growth in Vitro and in Vivo: A New Agent for Clinical Study.” Cancer Research 51:5579-55…
[cited by applicant]
Database Biosis [Online] Biosciences Information Service, Philadelphia, PA, US; Jackman A L et al: “ICI D1694, a Quinazoline Antifolate Thymidylate Synthase Inhibitor That Is a Potent Inhibitor of L1210 Tumor Cell Growt…
[cited by applicant]
Pawelczak et al., “Quinazoline antifolates inhibiting thymidylate synthase: synthesis of four oligo(L-.gamma.-glutamyl) conjugates of N10-propargyl -5,8-dideazafolic acid and Their enzyme inhibition”, J. Med. Chem. 32(1…
[cited by applicant]
Michalak et al., “Synthesis and Physicochemical Characterization of the Impurities of Pemetrexed Disodium, an Anticancer Drug”, Molecules, 20(6):10004-10031 (2105).
[cited by applicant]
Meesters et al., “Assessment of intracellular methotrexate and methotrexate-polyglutamate metabolite concentrations in erythrocytes by ultrafast matrix-assisted laser desorption/ionization triple quadrupole tandem mass …
[cited by applicant]
Pitts et al., “Interaction energy analyses of folate analog binding to human dihydrofolate reductase: contribution of the antifolate substructural regions to complex stability”, Drug Metabol. Drug Interact. 16(2):99-121…
[cited by applicant]
Ng et al., “Liposome-dependent 1-15 delivery of pteridine antifolates: a two-compartment growth inhibition assay for evaluating drug leakage and metabolism ”, Biochimica et Biophysica Acta, 98(2):261-268 (1989).
[cited by applicant]
Chattopadhyay et al., “Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications”, Molecular Cancer Therapeutics 6(2):404-417 (2007).
[cited by applicant]
Abraham et al., “Folate analogs. 33. Synthesis of folate and antifolate poly-.gamma.-glutamates by [(9-fluorenylmethoxy)oxy]carbonyl chemistry and biological evaluation of certain methotrexate polyglutamate polylysine c…
[cited by applicant]
Khan et al., “Methotrexate: a detailed review on drug delivery and clinical aspects”, Expert Opinion on Drug Delivery 9(2) 151-169 (2012).
[cited by applicant]
Lachelt et al., Synthetic polyglutamylation of dual-functional MTX ligands for enhanced combined cytotoxicity of poly(I:C) nanoplexes, Molecular Pharmaceutics (118): 2631-2639 (2014).
[cited by applicant]
Piper et al., “Syntheses of. alpha.-and. gamma.-substituted amides, peptides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism” J. Med. Chem. 25( 2): 182-187 (1982).
[cited by applicant]
Schultz, R. M., “Preclinical development of Alimta (Pemetrexed, LY231514), a multitargeted antifolate”, Progress in Drug Research, vol. 63, pp. 275-300. DOI: https://doi.org/10.1007/3-7643-7414-4_11, published in 2005.
[cited by applicant]
Szabo et al., “Cell-penetrating conjugates of pentaglutamylated methotrexate as potential anticancer drugs against resistant tumor cells” European Journal of Medicinal Chemistry 115:361-368 (2016).
[cited by applicant]
SciFinder® substance search alpha methotrexate diglutamate; Oct. 13, 2020 (Year 2020).
[cited by applicant]
Goolge Scholar Search—Shih pemetrexed Oct. 13, 2020 (Year: 2020).
[cited by applicant]
Barenholz, Y “Doxil®—The first FDA-approved nano-drug: Lessons learned” J. Controlled Release 160(2):117-134 (2012).
[cited by applicant]
Barrueco et al., “Facilitated Transport of Methotrexate Polyglutamates into Lysosomes Derived from S180 Cells.” The Journal of Biological Chemistry, 267(28):19986-19991 (1992).
[cited by applicant]
Immordino et al., ““Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential.”” Intl. J. Nanomed. 1 (3):297-315 (2006).
[cited by applicant]
Marchi et al., “Pralatrexate Pharmacology and Clinical Development,” Clin. Cancer Res. 19(24):6657-6661 (2013).
[cited by applicant]
Heinrich et al., “Comparison of the results obtained by ELISA and surface plasmon resonance for the determination of antibody affinity,” Journal of Immunological Methods, 352:13-22 (2010).
[cited by applicant]
Langer et al., “Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label Keynote-021 study,” Lancet Oncol. 17:1497-15…
[cited by applicant]
Nagai et al., “Production of a High-affinity Monoclonal Antibody Reactive with Folate Receptors Alpha and BetaMonoclonal Antibodies in Immunodiagnosis and Immunotherapy,” 34(3):181-190 (2015); doi.org/10.1089/mab.2014.0…
[cited by applicant]
Piper et al., “A synthetic approach to poly(.gamma.-glutamyl) conjugates of methotrexate” J. Med. Chem. 26(2):291-294 (1983).
[cited by applicant]
Piper et al., “Synthesis and antifolate activity of 5-methyl-5,10-dideaza analogs of aminopterin and folic acid and an alternative synthesis of 5,10-dideazatetrahydrofolic acid, a potent inhibitor of glycinamide ribonuc…
[cited by applicant]
Rosowsky et al., “Synthesis and in Vitro Antifolate Activity of Rotationally Restricted Aminopterin and Methotrexate Analogues,” Medicinal Chemistry 47:6958-6963 (2004).
[cited by applicant]
Raz et al., “Folylpoly-γ-glutamate synthetase: A key determinant of folate homeostasis and antifolate resistance in cancer,” Drug Resistance Updates, 28:43-64 (2016).
[cited by applicant]
Sulciner et al., “Resolvins suppress tumor growth and enhance cancer therapy,” Journal of Experimental Medicine 215(1):115-140 (2018).
[cited by applicant]
Pan et al., Pharmacology and Chemotherapy), Edition I, p. 102 paragraph 5 (Feb. 2000).
[cited by applicant]
Sakamoto et al., “Folylpolyglutamate synthase and γ-glutamyl hydrolase regulate leucovorin-enhanced 5-fluorouracil anticancer activity,” Biochem. and Biophys. Res. Comm. 365(4):801-807 (2008), ISSN 0006-291X.
[cited by applicant]
Paiardini et al., “Screening and In Vitro Testing of Antifolate Inhibitors of Human Cytosolic Serine Hydroxymethyltransferase,” ChemMedChem. 10(3): 490-497 (2015); doi:10.1002/cmdc.201500028.
[cited by applicant]
Schwendener chapt. 9, Liposomes in Biology and Medicine, 117-128 (2007).
[cited by applicant]
Hobl et al., “A short-chain methotrexate polyglutamate as outcome parameter in rheumatoid arthritis patients receiving methotrexate,” Clin. Exp. Rheum. 30:156-163 (2012).
[cited by applicant]
Purcell et al., “Novel antifolate Drugs,” Curr. Oncology Reports, Curr. Science, 5(2):114-125 (2003).
[cited by applicant]
Jolivet et al., “Synthesis, Retention, and Biological Activity of Methotrexate Polyglutamates in Cultured Human Breast Cancer Cells,” The Journal of Clinical Investigation, 70:351-360 (1982).
[cited by applicant]
Pignatello et al., “Effect of Liposomal Delivery on In Vitro Antitumor Activity of Lipophilic Conjugates of Methotrexate with Lipoamino Acids,” Drug Delivery 10:95-100 (2003).
[cited by applicant]
Shmeeda, H., et al., “Intracellular uptake and intracavitary targeting of folate-conjugated liposomes in a mouse lymphoma model with up-regulated folate receptors,” Mol. Cancer Ther., 5(4):818-824 (2006).
[cited by applicant]
Tseng, Y-L, et al., “Translocation of Liposomes into Cancer Cells by CellPenetrating Peptides Penetratin and Tat: A Kinetic and Efficacy Study,” Mol. Pharmacol. 62:864-872 (2002).
[cited by applicant]
Lehtinen, J., et al., “Pre-Targeting and Direct Immunotargeting of Liposomal Drug Carriers to Ovarian Carcinoma,” PLOS One, 7(7): 1-10 (2012).
[cited by applicant]
Li, T., “ A novel application of maleimide for advanced drug delivery: in vitro and in vivo evaluation of maleimide-modified pH-sensitive liposomes,” Intl J. Nanomed. 8:3855-3866 (2013).
[cited by applicant]
Paolino et al., “Gemcitabine-loaded PEGylated unilamellar liposomes vs GEMZAR®: Biodistribution, pharmacokinetic features and in vivo antitumor activity,” J Controlled Release 144:144-150 (2010).
[cited by applicant]
Pasut, G., et al., “Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid,” J. Controlled Rel. 127:239-248 (2008).
[cited by applicant]
Varshochian, et al., “Utilizing liposomes and lipid nanoparticles to overcome challenges in breast cancer treatment,” Clin. Lipidol. 9(5), 571-585 (2014).
[cited by applicant]
Wibowo, A., et al., “Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition,” PNAS 110(38):15180-15188 (2013).
[cited by applicant]
Rhee, et al., “Glutamyl hydrolase and the multitargeted antifolate LY231514,” Cancer Chemother. Pharmacol., 44:427-432 (1999).
[cited by applicant]
Chan et al., Advances in Experimental Medicine and Biology, vol. 620, Biochem. J. (1986) 236, 193-200 (Printed in Great Britain) (2007).
[cited by applicant]
Alexis et al.: “Nanoparticle technologies for cancer therapy”, Jan. 1, 2010 (Jan. 1, 2010, Drug Delivery In: Handbook of Experimental Pharmacology; vol. 197; pp. 55-86, ISSN 0171-2004; XP008182266.
[cited by applicant]
Allegra et al., “Enhanced Inhibition of Thymidylate Synthase by Methotrexate Polyglutamates,” J. Biological Chemistry, 260(17):9720-9726 (1985).
[cited by applicant]
Beutel et al., “Phase I study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor in patients with refractory solid tumors,” Clinical Cancer Research 11, 5487-5495 (2005).
[cited by applicant]
Desjardins et al., “Pharmacokinetics, safety, and efficacy of a liposome encapsulated thymidylate synthase inhibitor, OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo [f] quinazolin-9-yl)methyl]amino-1-oxo-2-isoind…
[cited by applicant]
Baggot et al., “Inhibition of 5-aminoimidazole-4-carboxamide ribotide transformylase, adenosine deaminase and 5′-adenylate deaminase by polyglutamates of methotrexate and oxidized folates and by 5-aminoimidazole-4-carbo…
[cited by applicant]