Folate-based radiotracers for PET imaging-update and perspectives

Molecules

Volumn 18, Issue 5, 2013, Pages 5005-5031

  Müller, Cristina ^a  

^a ETH Zurich   (Switzerland)

Author keywords

152Tb; 18F; 44Sc; 68Ga; Cancer; Folate receptor; Folic acid; Imaging; PET

Indexed keywords

FLUORINE; FOLATE RECEPTOR 1; FOLIC ACID; GALLIUM; RADIOPHARMACEUTICAL AGENT; TERBIUM; TUMOR PROTEIN;

ANIMAL; ARTICLE; CHEMISTRY; DRUG POTENTIATION; EXPERIMENTAL NEOPLASM; METABOLISM; METHODOLOGY; MOUSE; POSITRON EMISSION TOMOGRAPHY; RADIOGRAPHY; SYNTHESIS;

ANIMALS; FLUORINE RADIOISOTOPES; FOLATE RECEPTOR 1; FOLIC ACID; GALLIUM ISOTOPES; MICE; NEOPLASM PROTEINS; NEOPLASMS, EXPERIMENTAL; POSITRON-EMISSION TOMOGRAPHY; RADIOPHARMACEUTICALS; TERBIUM;

EID: 84878269164     PISSN: None     EISSN: 14203049     Source Type: Journal    
DOI: 10.3390/molecules18055005     Document Type: Review

References (104)

1. Mittra, E.; Quon, A. Positron emission tomography/computed tomography: The current technology and applications. Radiol. Clin. North Am. 2009, 47, 147-160.
2. Kramer-Marek, G.; Capala, J. Can PET imaging facilitate optimization of cancer therapies? Curr. Pharm. Des. 2012, 18, 2657-2669.
3. 3-octreotide PET in neuroendocrine tumors: Comparison with somatostatin receptor scintigraphy and CT. J. Nucl. Med. 2007, 48, 508-518. (Pubitemid 47571404)
4. 68Ga-DOTATATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors. J. Nucl. Med. 2010, 51, 1349-1356.
5. 68Ga-DOTATATE PET/CT in suspected neuroendocrine tumors. J. Nucl. Med. 2012, 53, 1686-1692.
6. Müller, C. Folate based radiopharmaceuticals for imaging and therapy of cancer and inflammation. Curr. Pharm. Des. 2012, 18, 1058-1083.
7. Antony, A.C. Folate receptors. Ann. Rev. Nutr. 1996, 16, 501-521. (Pubitemid 26286863)
8. Ratnam, M.; Marquardt, H.; Duhring, J.L.; Freisheim, J.H. Homologous membrane folate binding-proteins in human-placenta-Cloning and sequence of a cDNA. Biochemistry 1989, 28, 8249-8254. (Pubitemid 19252909)
9. Shen, F.; Ross, J.F.; Wang, X.; Ratnam, M. Identification of a novel folate receptor, a truncated receptor, and receptor type β in hematopoietic cells: cDNA cloning, expression, immunoreactivity, and tissue specificity. Biochemistry 1994, 33, 1209-1215. (Pubitemid 24072451)
10. Shen, F.; Wu, M.; Ross, J.F.; Miller, D.; Ratnam, M. Folate receptor type γ is primarily a secretory protein due to lack of an efficient signal for glycosylphosphatidylinositol modification-Protein characterization and cell type specificity. Biochemistry 1995, 34, 5660-5665.
11. Spiegelstein, O.; Eudy, J.D.; Finnell, R.H. Identification of two putative novel folate receptor genes in humans and mouse. Gene 2000, 258, 117-125.
12. Garin-Chesa, P.; Campbell, I.; Saigo, P.E.; Lewis, J.L.; Old, L.J.; Rettig, W.J. Trophoblast and ovarian cancer antigen LK26-Sensitivity and specificity in immunopathology and molecular identification as a folate-binding protein. Am. J. Pathol. 1993, 142, 557-567. (Pubitemid 23057469)
13. Parker, N.; Turk, M.J.; Westrick, E.; Lewis, J.D.; Low, P.S.; Leamon, C.P. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal. Biochem. 2005, 338, 284-293. (Pubitemid 40312593)
14. Low, P.S.; Kularatne, S.A. Folate-targeted therapeutic and imaging agents for cancer. Curr. Opin. Chem. Biol. 2009, 13, 256-262.
15. Xia, W.; Hilgenbrink, A.R.; Matteson, E.L.; Lockwood, M.B.; Cheng, J.X.; Low, P.S. A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. Blood 2009, 113, 438-446.
16. Weitman, S.D.; Lark, R.H.; Coney, L.R.; Fort, D.W.; Frasca, V.; Zurawski, V.R.; Kamen, B.A. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res. 1992, 52, 3396-3401.
17. Weitman, S.D.; Weinberg, A.G.; Coney, L.R.; Zurawski, V.R.; Jennings, D.S.; Kamen, B.A. Cellular localization of the folate receptor: Potential role in drug toxicity and folate homeostasis. Cancer Res. 1992, 52, 6708-6711.
18. 99mTc-radiofolate. J. Nucl. Med. 2008, 49, 310-317. (Pubitemid 351225671)
19. Holm, J.; Hansen, S.I.; Hoiermadsen, M.; Bostad, L. A high-affinity folate binding-protein in proximal tubule cells of human kidney. Kidney Int. 1992, 41, 50-55.
20. Sandoval, R.M.; Kennedy, M.D.; Low, P.S.; Molitoris, B.A. Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy. Am. J. Physiol. Cell Physiol. 2004, 287, C517-C526. (Pubitemid 38955243)
21. Birn, H.; Spiegelstein, O.; Christensen, E.I.; Finnell, R.H. Renal tubular reabsorption of folate mediated by folate binding protein 1. J. Am. Soc. Nephrol. 2005, 16, 608-615. (Pubitemid 41725097)
22. Low, P.S.; Henne, W.A.; Doorneweerd, D.D. Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. Acc. Chem. Res. 2008, 41, 120-129.
23. Iwakiri, S.; Sonobe, M.; Nagai, S.; Hirata, T.; Wada, H.; Miyahara, R. Expression status of folate receptor alpha is significantly correlated with prognosis in non-small-cell lung cancers. Ann. Surg. Oncol. 2008, 15, 889-899.
24. Toffoli, G.; Russo, A.; Gallo, A.; Cernigoi, C.; Miotti, S.; Sorio, R.; Tumolo, S.; Boiocchi, M. Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer. Int. J. Cancer 1998, 79, 121-126. (Pubitemid 28201681)
25. Brown Jones, M.; Neuper, C.; Clayton, A.; Mariani, A.; Konecny, G.; Thomas, M.B.; Keeney, G.; Hartmann, L.; Podratz, K.C. Rationale for folate receptor alpha targeted therapy in "high risk" endometrial carcinomas. Int. J. Cancer 2008, 123, 1699-1703.
26. Hartmann, L.C.; Keeney, G.L.; Lingle, W.L.; Christianson, T.J.; Varghese, B.; Hillman, D.; Oberg, A.L.; Low, P.S. Folate receptor overexpression is associated with poor outcome in breast cancer. Int. J. Cancer 2007, 121, 938-942. (Pubitemid 47101628)
27. D'Angelica, M.; Ammori, J.; Gonen, M.; Klimstra, D.S.; Low, P.S.; Murphy, L.; Weiser, M.R.; Paty, P.B.; Fong, Y.; Dematteo, R.P.; Allen, P.; Jarnagin, W.R.; Shia, J. Folate receptor-α expression in resectable hepatic colorectal cancer metastases: Patterns and significance. Mod. Pathol. 2011, 24, 1221-1228.
28. Kinne, R.W.; Brauer, R.; Stuhlmuller, B.; Palombo-Kinne, E.; Burmester, G.R. Macrophages in rheumatoid arthritis. Arthritis Res. 2000, 2, 189-202. (Pubitemid 32223726)
29. Tak, P.P.; Smeets, T.J.; Daha, M.R.; Kluin, P.M.; Meijers, K.A.; Brand, R.; Meinders, A.E.; Breedveld, F.C. Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum. 1997, 40, 217-225. (Pubitemid 27114085)
30. Paulos, C.M.; Turk, M.J.; Breur, G.J.; Low, P.S. Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis. Adv. Drug Deliv. Rev. 2004, 56, 1205-1217. (Pubitemid 38496516)
31. Ke, C.Y.; Mathias, C.J.; Green, M.A. Folate-receptor-targeted radionuclide imaging agents. Adv. Drug Deliv. Rev. 2004, 56, 1143-1160. (Pubitemid 38499700)
32. Müller, C.; Schibli, R. Folic acid conjugates for nuclear imaging of folate receptor-positive cancer. J. Nucl. Med. 2011, 52, 1-4.
33. 111In-DTPA-folate as a receptor-targeted diagnostic agent for ovarian cancer: Initial clinical results. J. Nucl. Med. 2003, 44, 700-707. (Pubitemid 39655203)
34. 99mTc-EC20 imaging for identifying patients with folate receptor-positive solid tumors. J. Nucl. Med. 2008, 49, 899-906. (Pubitemid 351793430)
35. Edelman, M.J.; Harb, W.A.; Pal, S.E.; Boccia, R.V.; Kraut, M.J.; Bonomi, P.; Conley, B.A.; Rogers, J.S.; Messmann, R.A.; Garon, E.B. Multicenter trial of EC145 in advanced, folate-receptor positive adenocarcinoma of the lung. J. Thorac. Oncol. 2012, 7, 1618-1621.
36. Jiang, L.; Zeng, X.; Wang, Z.; Chen, Q. Cell line cross-contamination: KB is not an oral squamous cell carcinoma cell line. Eur. J. Oral Sci. 2009, 117, 90-91.
37. 13N radiolabels for positron emission tomography. Angew. Chem. Int. Ed. Engl. 2008, 47, 8998-9033.
38. Antunes, P.; Ginj, M.; Zhang, H.; Waser, B.; Baum, R.P.; Reubi, J.C.; Maecke, H. Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals? Eur. J. Nucl. Med. Mol. Imaging 2007, 34, 982-993. (Pubitemid 46919547)
39. 68Ga-PET: A powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals. Contrast Media Mol. Imaging 2008, 3, 67-77.
40. 68Ga for medical application. J. Nucl. Med. 2007, 48, 1741-1748. (Pubitemid 47572722)
41. 66Ga as an isotope for PET imaging and quantification. Med. Phys. 1997, 24, 317-326. (Pubitemid 27084038)
42. 18F for PET imaging of folate receptor-positive tumors. J. Nucl. Med. 2006, 47, 1153-1160. (Pubitemid 47544910)
43. F-labeled folic acid derivative. Bioconjug. Chem. 2008, 19, 2462-2470.
44. F-labeled folic acid derivative with improved properties for the PET imaging of folate receptor-positive tumors. J. Nucl. Med. 2010, 51, 1756-1762.
45. 18F]fluoro-deoxy-glucose folate: A novel PET radiotracer with improved in vivo properties for folate receptor targeting. Bioconjug. Chem. 2012, 23, 805-813.
46. Betzel, T.; Müller, C.; Groehn, V.; Müller, A.; Reber, J.; Fischer, C.R.; Krämer, S.D.; Schibli, R.; Ametamey, S.M. Radiosynthesis and preclinical evaluation of 3'-aza-2'-[18F]fluorofolic acid: A novel PET radiotracer for folate receptor targeting. Bioconjug. Chem. 2013, 24, 205-214.
47. 68Ga-labeled Ga(III)- deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals. Nucl. Med. Biol. 2003, 30, 725-731. (Pubitemid 37123129)
48. Mathias, C.J.; Wang, S.; Lee, R.J.; Waters, D.J.; Low, P.S.; Green, M.A. Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate. J. Nucl. Med. 1996, 37, 1003-1008. (Pubitemid 126447142)
49. 67Ga-deferoxamine-folate to folate-receptor-positive human KB tumor xenografts. Nucl. Med. Biol. 1999, 26, 23-25. (Pubitemid 29030517)
50. Fani, M.; Wang, X.; Nicolas, G.; Medina, C.; Raynal, I.; Port, M.; Maecke, H.R. Development of new folate-based PET radiotracers: Preclinical evaluation of Ga-DOTA-folate conjugates. Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 108-119.
51. 68Ga-NODAGA-folate conjugates. Mol. Pharm. 2012, 9, 1136-1145.
52. Müller, C.; Zhernosekov, K.; Koster, U.; Johnston, K.; Dorrer, H.; Hohn, A.; van der Walt, N.T.; Türler, A.; Schibli, R. A unique matched quadruplet of terbium radioisotopes for PET and SPECT and for α- and β-radionuclide therapy: An in vivo proof-of-concept study with a new receptor-targeted folate derivative. J. Nucl. Med. 2012, 53, 1951-1959.
53. 44Sc-DOTA-folate conjugate. J. Nucl. Med. Submitted.
54. Allen, B.J.; Goozee, G.; Sarkar, S.; Beyer, G.; Morel, C.; Byrne, A.P. Production of terbium-152 by heavy ion reactions and proton induced spallation. Appl. Radiat. Isot. 2001, 54, 53-58.
55. Köster, U.; ISOLDE Collaboration. ISOLDE target and ion source chemistry. Radiochim. Acta 2001, 89, 749-756.
56. Majkowska-Pilip, A.; Bilewicz, A. Macrocyclic complexes of scandium radionuclides as precursors for diagnostic and therapeutic radiopharmaceuticals. J. Inorg. Biochem. 2011, 105, 313-320.
57. 44Sc a potential radionuclide for PET? Appl. Radiat. Isot. 2012, 70, 2669-2676.
58. 44Sc-DOTA-puromycin. Mol. Imaging Biol. 2013, 15, 79-86.
59. 44Sc generator system. Curr. Radiopharm. 2012, 5, 187-201.
60. 44gSc from natural calcium. Appl. Radiat. Isot. 2012, 70, 1526-1530.
61. F for in vivo PET imaging. J. Labelled Compd. Radiopharm. 1997, 39, 319-330. (Pubitemid 27149924)
62. Missimer, J.; Madi, Z.; Honer, M.; Keller, C.; Schubiger, A.; Ametamey, S.M. Performance evaluation of the 16-module quad-HIDAC small animal PET camera. Phys. Med. Biol. 2004, 49, 2069-2081. (Pubitemid 38735492)
63. 18F]fluorobenzene and pyridinecarbohydrazide-folates as potential PET radiopharmaceuticals. J. Labelled Compd. Radiopharm. 2006, 49, 125-137. (Pubitemid 43384887)
64. 18F]fluoroisonicotinic acid hydrazide and initial biological evaluation. Nucl. Med. Biol. 2002, 29, 817-823. (Pubitemid 35346902)
65. 111In]DTPA- folate for use as a tumor-targeted radiopharmaceutical. Bioconjug. Chem. 1997, 8, 673-679. (Pubitemid 27416080)
66. 99mTc-HYNIC-folate: A novel receptor-based targeted radiopharmaceutical for tumor imaging. J. Nucl. Med. 1999, 40, 1563-1569. (Pubitemid 29428942)
67. Al Jammaz, I.; Al-Otaibi, B.; Amer, S.; Okarvi, S.M. Rapid synthesis and in vitro and in vivo evaluation of folic acid derivatives labeled with fluorine-18 for PET imaging of folate receptor-positive tumors. Nucl. Med. Biol. 2011, 38, 1019-1028.
68. Westerhof, G.R.; Schornagel, J.H.; Kathmann, I.; Jackman, A.L.; Rosowsky, A.; Forsch, R.A.; Hynes, J.B.; Boyle, F.T.; Peters, G.J.; Pinedo, H.M.; et al. Carrier- and receptor-mediated transport of folate antagonists targeting folate-dependent enzymes: Correlates of molecular-structure and biological activity. Mol. Pharmacol. 1995, 48, 459-471.
69. Tornoe, C.W.; Christensen, C.; Meldal, M. Peptidotriazoles on solid phase: [1,2,3]-Triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 2002, 67, 3057-3064. (Pubitemid 34457265)
70. Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise huisgen cycloaddition process: Copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes. Angew. Chem. Int. Ed. Engl. 2002, 41, 2596-2599. (Pubitemid 34803480)
71. 18F]fluoropeptides using CuI catalyzed 1,3-dipolar cycloaddition. Tetrahedron Lett. 2006, 47, 6681-6684. (Pubitemid 44176106)
72. 3-labeled N(tau)-histidine folate derivative with its isostructural, clicked 1,2,3-triazole analogue. Bioconjug. Chem. 2008, 19, 1689-1695.
73. Mindt, T.L.; Müller, C.; Stuker, F.; Salazar, J.F.; Hohn, A.; Müggler, T.; Rudin, M.; Schibli, R. A "click chemistry" approach to the efficient synthesis of multiple imaging probes derived from a single precursor. Bioconjug. Chem. 2009, 20, 1940-1949.
74. 18F]FDG for PET imaging of folate receptor-positive tumors. Nucl. Med. Biol. 2012, 39, 864-870.
75. 111In-DTPA-methotrexate. Cancer Biother. Radiopharm. 1998, 13, 177-184. (Pubitemid 28359720)
76. F-labeling and glycosylation by click chemistry. Carbohydr. Res. 2009, 344, 753-761.
77. F-glycopeptides as effective imaging probes for positron emission tomography. Angew. Chem. Int. Ed. Engl. 2010, 49, 976-979.
78. F-labeling of folic acid for PET application. Synthesis 2011, 2011, 3639-3648.
79. Curtin, N.J.; Hughes, A.N. Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncol. 2001, 2, 298-306. (Pubitemid 33591568)
80. Paz-Ares, L.; Bezares, S.; Tabernero, J.M.; Castellanos, D.; Cortes-Funes, H. Review of a promising new agent-Pemetrexed disodium. Cancer 2003, 97, 2056-2063. (Pubitemid 36397246)
81. Müller, C.; Brühlmeier, M.; Schubiger, A.P.; Schibli, R. Effects of antifolate drugs on the cellular uptake of radiofolates in vitro and in vivo. J. Nucl. Med. 2006, 47, 2057-2064. (Pubitemid 47544994)
82. 111In-DTPA-folate in mice with folate receptor-positive ovarian cancer. J. Nucl. Med. 2008, 49, 623-629. (Pubitemid 351520611)
83. 99mTc-EC20 in xenografted and syngeneic tumor-bearing mice. Mol. Pharm. 2010, 7, 597-604.
84. Müller, C.; Mindt, T.L.; de Jong, M.; Schibli, R. Evaluation of a novel radiofolate in tumour-bearing mice: Promising prospects for folate-based radionuclide therapy. Eur. J. Nucl. Med. Mol. Imaging 2009, 36, 938-946.
85. 67Ga-DOTA-Bz-folate-Investigations of methods to improve the tissue distribution of radiofolates. Nucl. Med. Biol. 2011, 38, 715-723.
86. 68Ga- labeled pteroic acid-based PET tracer for tumor imaging via the folate receptor. Recent Results Cancer Res. 2013, 194, 257-267.
87. 111In-DTPA conjugate of pteroic acid. J. Am. Chem. Soc. 2005, 127, 7421-7426. (Pubitemid 40746027)
88. 99mTc-pteroate radiotracers for folate receptor-positive tumour targeting. Eur. J. Nucl. Med. Mol Imaging 2006, 33, 1007-1016. (Pubitemid 44215666)
89. Guo, H.; Xie, F.; Zhu, M.; Li, Y.; Yang, Z.; Wang, X.; Lu, J. The synthesis of pteroyl-lys conjugates and its application as technetium-99m labeled radiotracer for folate receptor-positive tumor targeting. Bioorg. Med. Chem. Lett. 2011, 21, 2025-2029.
90. Leamon, C.P.; DePrince, R.B.; Hendren, R.W. Folate-mediated drug delivery: Effect of alternative conjugation chemistry. J. Drug Targeting 1999, 7, 157-169. (Pubitemid 30028960)
91. Leamon, C.P.; You, F.; Santhapuram, H.K.; Fan, M.; Vlahov, I.R. Properties influencing the relative binding affinity of pteroate derivatives and drug conjugates thereof to the folate receptor. Pharm. Res. 2009, 26, 1315-1323.
92. Theti, D.S.; Bavetsias, V.; Skelton, L.A.; Titley, J.; Gibbs, D.; Jansen, G.; Jackman, A.L. Selective delivery of CB300638, a cyclopenta[g]quinazoline- based thymidylate synthase inhibitor into human tumor cell lines overexpressing the alpha-isoform of the folate receptor. Cancer Res. 2003, 63, 3612-3618. (Pubitemid 36793043)
93. 177Lu-radionuclide tumor therapy in mice. J. Nucl. Med. 2013, 54, 124-131.
94. Dumelin, C.E.; Trüssel, S.; Buller, F.; Trachsel, E.; Bootz, F.; Zhang, Y.; Mannocci, L.; Beck, S.C.; Drumea-Mirancea, M.; Seeliger, M.W.; et al. A portable albumin binder from a DNA-encoded chemical library. Angew. Chem. Int. Ed. Engl. 2008, 47, 3196-3201.
95. 177Lu for targeted radionuclide therapy. Nucl. Med. Biol. 2011, 38, 917-924.
96. Turk, M.J.; Breur, G.J.; Widmer, W.R.; Paulos, C.M.; Xu, L.C.; Grote, L.A.; Low, P.S. Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis. Arthritis Rheum. 2002, 46, 1947-1955. (Pubitemid 34774528)
97. Piscaer, T.M.; Müller, C.; Mindt, T.L.; Lubberts, E.; Verhaar, J.A.; Krenning, E.P.; Schibli, R.; de Jong, M.; Weinans, H. Imaging of activated macrophages in experimental osteoarthritis using folate-targeted animal single-photon-emission computed tomography/computed tomography. Arthritis Rheum. 2011, 63, 1898-1907.
98. Ayala-Lopez, W.; Xia, W.; Varghese, B.; Low, P.S. Imaging of atherosclerosis in apoliprotein E knockout mice: Targeting of a folate-conjugated radiopharmaceutical to activated macrophages. J. Nucl. Med. 2010, 51, 768-774.
99. 99mTc-labeled folate conjugate targeted to folate receptor positive macrophages. Mol. Pharm. 2012, 9, 1435-1440.
100. Yi, Y.S.; Ayala-Lopez, W.; Kularatne, S.A.; Low, P.S. Folate-targeted hapten immunotherapy of adjuvant-induced arthritis: Comparison of hapten potencies. Mol. Pharm. 2009, 6, 1228-1236.
101. Lu, Y.; Stinnette, T.W.; Westrick, E.; Klein, P.J.; Gehrke, M.A.; Cross, V.A.; Vlahov, I.R.; Low, P.S.; Leamon, C.P. Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate. Arthritis Res. Ther. 2011, 13, R56.
102. Henne, W. A.; Kularatne, S. A.; Ayala-Lopez, W.; Doorneweerd, D.D.; Stinnette, T.W.; Lu, Y.; Low, P.S. Synthesis and activity of folate conjugated didemnin B for potential treatment of inflammatory diseases. Bioorg. Med. Chem. Lett. 2012, 22, 709-712.
103. Nagai, T.; Kyo, A.; Hasui, K.; Takao, S.; Matsuyama, T. Efficacy of an immunotoxin to folate receptor beta in the intra-articular treatment of antigen-induced arthritis. Arthritis Res. Ther. 2012, 14, R106.
104. Feng, Y.; Shen, J.; Streaker, E.D.; Lockwood, M.; Zhu, Z.; Low, P.S.; Dimitrov, D.S. A folate receptor beta-specific human monoclonal antibody recognizes activated macrophage of rheumatoid patients and mediates antibody-dependent cell-mediated cytotoxicity. Arthritis Res. Ther. 2011, 13, R59.