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(12) United States Patent (10) Patent No.: US 8,835,617 B2 Luban Et Al US008835617B2 (12) United States Patent (10) Patent No.: US 8,835,617 B2 Luban et al. (45) Date of Patent: Sep. 16, 2014 (54) POLYNUCLEOTIDES ENCODINGA HUMAN 2007/01051 22 A1 5/2007 Ota et al. TRIM-CYPFUSION POLYPEPTIDE, 2007/O141679 A1 6/2007 Sodroski et al. 2007/O185O17 A1 8/2007 Aggarwal et al. COMPOSITIONS THEREOF, AND METHODS 2008/004.5454 A1 2/2008 Luban et al. OF USING SAME (75) Inventors: Jeremy Luban, New York, NY (US); FOREIGN PATENT DOCUMENTS Martha Neagu, Gaithersburg, MD (US) EP 336523 A1 10, 1989 (73) Assignee: The Trustees of Columbia University WO WO-9011092 A1 10, 1990 in the City of New York, New York, NY WO WO-2006/O14422 2, 2006 (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Brennan et al. TRIMCyp expression in Old World primates Macaca patent is extended or adjusted under 35 nemestrina and Macaca fascicularis. PNAS, Mar. 4, 2008, vol. 105, U.S.C. 154(b) by 429 days. No. 9, pp. 3569-3574.* (21) Appl. No.: 13/128,143 Liao et al. A novel fusion gene, TRIM5-Cyclophilin A in the pig tailed macaque determines its susceptibility to HIV-1 infection. (22) PCT Filed: Nov. 6, 2009 AIDS 2007, vol. 21, Suppl. 8, S19-S26.* (86). PCT No.: PCT/US2O09/063481 Extended European Search Report mailed Apr. 10, 2012 for Euro pean Application No. 09825443.6, filed Nov. 6, 2009 (9 pages). S371 (c)(1), Neagu et al., “Potent inhibition of HIV-1 by TRIM5-cyclophilin (2), (4) Date: Dec. 1, 2011 fusion proteins engineered from Human components.” The Journal of (87) PCT Pub. No.: WO2010/054141 Clinical Investigation, vol. 119, pp. 3035-3047 (Oct. 2009). Nisole et al., “A Trim5-cycliphilin A fusion protein found in owl PCT Pub. Date: May 14, 2010 monkey kidney cells can restrict HIV-1.” PNAS, vol. 101, pp. 13324 (65) Prior Publication Data 13328 (Sep. 7, 2004). Sayah et al., “Cyclophilin A retrotransposition into TRIM5 explains US 2012/0095444 A1 Apr. 19, 2012 owl monkey resistance to HIV-1.” Nature, vol. 430, pp. 569-573 (Jul. 2004). International Search Report mailed on May 27, 2010, for Interna Related U.S. Application Data tional Application No. PCT/US09/63481 filed Nov. 6, 2009. Liao et al., Full = Trim57 cyclophilin A V1 Fusion protein. Jan. 9. (60) Provisional application No. 61/112,013, filed on Nov. UniProt Accession No. AOSE27 MACNE. 6, 2008, provisional application No. 61/240,505, filed Mortellaro et al., “Ex. vivo gene therapy with lentiviral vectors res on Sep. 8, 2009. cues adenosine deanimase (ADA)-deficient mice and corrects their immune and metabolic defects.” Blood, vol. 108, pp. 2979-2988 (51) Int. Cl. (Nov. 1, 2006). C7H 2L/04 (2006.01) Written Opinion mailed on May 27, 2010, for International Applica C07K 9/00 (2006.01) tion No. PCT/US09/63481 filed Nov. 6, 2009. Ambrose, Z., KewalRamani, V.N., BieniaSZ, P. D., and Hatziioannou, CI2N 5/62 (2006.01) T. (2007). HIV/AIDS: in search of an animal model. Trends in CI2N 15/63 (2006.01) biotechnology 25, 333-337. A6 IK 4.8/00 (2006.01) An, D. S., et al. Stable reduction of CCR5 by RNAi through C07K I4/47 (2006.01) hematopoietic stem cell transplant in non-human primates. Proc Natl CI2N 9/90 (2006.01) Acad Sci 104, 13110-13115 (2007). A61 K38/00 (2006.01) (Continued) (52) U.S. Cl. CPC ............. C07K 14/47 (2013.01); C12N 2830/85 Primary Examiner — Louise Humphrey (2013.01); A61K 48/005 (2013.01); A0IK (74) Attorney, Agent, or Firm — Wilmer Cutler Pickering 221 7/15 (2013.01); A6 IK 38/00 (2013.01); Hale and Dorr LLP CI2N 284.0/206 (2013.01); A0IK 2227/105 (57) ABSTRACT (2013.01); C12N 9/90 (2013.01); C07K A nucleic acid is provided which encodes a human TRIM 2319/00 (2013.01); A0IK 2207/12 (2013.01); cyclophilin A fusion sequence encoding a human TRIM CI2N 2740/16043 (2013.01); C12N 2830/60 CypA fusion protein which is active as an anti-viral agent, and (2013.01); A0I K2267/0337 (2013.01); A0IK in particular, as an anti-HIV-1 agent. Also provided is a nucleic acid encoding a polypeptide having both TRIM activ 2217/052 (2013.01); C12N 2740/1601 1 ity and cyclophilin activity. Also provided is an isolated poly (2013.01) nucleotide encoding a human TRIM-CypA fusion protein, or USPC ... 536/23.4:530/350; 530/387.9; 435/320.1; variants thereof retaining the TRIM and cyclophilin A activi 435/325 ties. Also provided are compositions thereof, antibodies that (58) Field of Classification Search specifically bind thereto, and vectors and host cells compris CPC. A61 K48/005; C07K 14/47; C07K 2319/00; ing the nucleic acid or polypeptide. In addition, methods are C12N 15700; C12N 15/63 provided for treating or preventing viral infection, or reducing See application file for complete search history. viral load in a subject comprising administering the nucleic acid, polypeptide, vector, or composition to the Subject in an (56) References Cited amount effective to treat or prevent the viral infection. In some embodiments, the viral infection is HIV-I infection, U.S. PATENT DOCUMENTS hepatitis C infection, pox virus infection, vaccinia virus infec 5,399,346 A 3, 1995 Anderson et al. tion, or HTLV infection. 2006/0134663 A1 6, 2006 Harkin et al. 12 Claims, 75 Drawing Sheets US 8,835,617 B2 Page 2 (56) References Cited Berthoux, L., Towers, G. J., Gurer, C., Salomoni, P., Pandolfi, P. P. and Luban, J. (2003). As(2)O(3) enhances retroviral reverse tran OTHER PUBLICATIONS scription and counteracts Refl antiviral activity. JVirol 77, 3167 Anderson, J. and Akkina, R. Human immunodeficiency virus type 1 3180. restriction by human-rhesus chimeric tripartite motif 5alpha (TRIM Besnier, C., Takeuchi, Y., and Towers, G. (2002). Restriction of 5alpha) in CD34(+) cell-derived macrophages in vitro and in T cells lentivirus in monkeys. Proc Natl Acad Sci USA99, 11920-1 1925. in vivo in severe combined immunodeficient (SCID-hu) mice trans Besnier, C., Ylinen, L., Strange, B., Lister, A., Takeuchi, Y. Goff, S. planted with human fetal tissue. Human Gene Therapy 9, 217-228 P. and Towers, G. J. (2003). Characterization of murine leukemia (2008). virus restriction in mammals. J Virol 77, 13403-13406. Anderson, J. and Akkina, R. TRIM5alpharh expression restricts Bieniasz, P. D., “Restriction factors: a defense against retroviral HIV-1 infection in lentiviral vector-transduced CD34+-cell-derived infection.” Trends Microbial 11:286-291 (2003). macrophages. Mol Ther 12, 687-696 (2005). Bishop, K. N. Bock, M., Towers, G., and Stoye, J. P. (2001). Identi Anderson, J. L., Campbell, E. M., Wu, X. Vandegraaff, N., Engel fication of the regions of Fvl necessary for murine leukemia virus man, A., and Hope, T. J. (2006). Proteasome inhibition reveals that a restriction. J Virol 75, 5182-5 188. functional preintegration complex intermediate can be generated dur Blunt, T., Gell, D., Fox, M., Taccioli, G. E., Lehmann, A.R., Jackson, ing restriction by diverse TRIM5 proteins. J Virol 80,9754-9760. S. P., and Jeggo, P. A. (1996). Identification of a nonsense mutation in Anderson, J., and Akkina, R. (2005). CXCR4 and CCR5 shRNA the carboxyl-terminal region of DNA-dependent protein kinase cata transgenic CD34+ cell derived macrophages are functionally normal lytic subunit in the scid mouse. Proc Natl AcadSci USA93, 10285 and resist HIV-1 infection. Retrovirology 2, 53, 1-11. 1029O. Anderson, J., Li, M.J., Palmer, B., Remling, L., Li, S., Yam, P., Yee, Boden, D., Pusch, O. and Ramratnam, B. Overcoming HIV-1 resis J. K. Rossi, J., Zaia, J., and Akkina, R. (2007). Safety and efficacy of tance to RNA interference. Front Biosci 12 (2007), 14pgs. a lentiviral vector containing three anti-HIV genes—CCR5 Boden, D., Pusch, O., Lee, F. Tucker, L., and Ramratnam, B. (2003). ribozyme, tat-rev siRNA, and TAR decoy in SCID-humouse-de Human immunodeficiency virus type 1 escape from RNA interfer ence. J Virol 77, 11531-11535. rived T cells. Mol Ther 15, 1182-1188. Bogerd, H. P. Doehle, B. P. Wiegand, H. L., and Cullen, B. R. Anderson, P., Phillips, K., Stoecklin, G., and Kedersha, N. (2004). (2004). A single amino acid difference in the host APOBEC3G pro Post-transcriptional regulation of proinflammatory proteins. J tein controls the primate species specificity of HIV type 1 virion Leukoc Biol 76, 42-47. infectivity factor. Proc Natl Acad Sci USA 101, 3770-3774. Arthos, J., Cicala, C., Martinelli, E., Macleod, K. Van Ryk, D., Wei, Boone, L. R., Innes, C. L., and Heitman, C. K. (1990). Abrogation of D., Xiao, Z., Veenstra, T. D., Conrad, T. P. Lempicki, R. A., et al. FV-1 restriction by genome-deficient virions produced by a retrovirus (2008). HIV-1 envelope protein binds to and signals through integrin packaging cell line. JVirol 64, 3376-3381. alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Bosco, D. A., Eisenmesser, E.Z., Pochapsky, S., Sundquist, W.I., and Nature immunology 9, 301-309. Kern, D. (2002). Catalysis of cis/trans isomerization in native HIV-1 Asaoka, K., Ikeda, K. Hishinuma, T., Horie-lnoue, K., Takeda, S., capsid by human cyclophilin A. Proc Natl AcadSci USA99, 5247 and Inoue, S. (2005). A retrovirus restriction factor TRIM5 alpha is 5252. transcriptionally regulated by interferons. Biochemical and bio Bosma, G.C., Fried, M., Custer, R. P. Carroll, A., Gibson, D.M., and physical research communications 338, 1950-1956. Bosma, M. J. (1988). Evidence of functional lymphocytes in some Baenziger, S., et al.
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