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(12) Patent Application Publication (10) Pub. No.: US 2016/0340659 A1 SHOSEYOV Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0340659 A1 SHOSEYOV Et Al US 2016.0340659A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0340659 A1 SHOSEYOV et al. (43) Pub. Date: Nov. 24, 2016 (54) ACTIN BINDING PEPTIDES AND (86). PCT No.: PCT/IL2O15/05O108 COMPOSITIONS COMPRISING SAME FOR S 371 (c)(1) INHIBITING ANGOGENESIS AND (2) Date: Jul. 21, 2016 TREATING MEDICAL CONDITIONS ASSOCATED WITH SAME Related U.S. Application Data (71) Applicant: YISSUM RESEARCH AND (60) Provisional application No. 61/933,363, filed on Jan. DEVELOPMENT COMPANY OF 30, 2014. THE HEBREW UNIVERSITY OF Publication Classification JERUSALEM LTD., Jerusalem (IL) (51) Int. Cl. (72) Inventors: Oded SHOSEYOV, Karme Yosef (IL); CI2N 9/22 (2006.01) Betty SCHWARTZ, Rechovot (IL); (52) U.S. Cl Shani DORON, Rechovot (IL): Liron CPC ............... CI2N 9/22 (2013.01); C12Y-301/27 NESIEL, Rechovot (IL); Assaf (2013.01); A6 IK 38/00 (2013.01) FRIEDLER, Mevasseret Zion (IL); s (IL); Levava ROIZ, Kiryat-Ono (IL); Patricia SMIRNOFF, Rehovot (IL); The present invention, in some embodiments thereof, relates Iris LEWIN, Mevaseret Zion (IL) to biologically active peptides and, more particularly, but not exclusively, to peptides from T2 RNase (RNASET2) having (21) Appl. No.: 15/113,187 actin binding, pharmaceutical compositions comprising the same, therapeutic use thereof and methods for their produc (22) PCT Filed: Jan. 29, 2015 tion. Patent Application Publication Nov. 24, 2016 Sheet 1 of 27 US 2016/0340659 A1 Patent Application Publication Nov. 24, 2016 Sheet 2 of 27 US 2016/0340659 A1 º|www.nH Hw Patent Application Publica tion Nov. 24, 2016 Sheet 3 of 27 US 2016/0340659 A1 a rives caves ar, or---------- - in rain rasra in a ra.------------------------- Patent Application Publication US 2016/0340659 A1 Patent Application Publication Nov. 24, 2016 Sheet 5 of 27 US 2016/0340659 A1 F.G. 3 Patent Application Publication Nov. 24, 2016 Sheet 6 of 27 US 2016/0340659 A1 3. 8 Patent Application Publication Nov. 24, 2016 Sheet 7 of 27 US 2016/0340659 A1 G. 5A xtr2-49 xxx A103-Q159 E a () ~~~ -0.29 O) Protein conc. (ng/100ul) xxt 2-49 xxx 808-K33 ... O 200 OO 600 -0.2 - Protein conc. ng/100ul) G. 53 Patent Application Publication Nov. 24, 2016 Sheet 8 of 27 US 2016/0340659 A1 15: w Angiot pep, KO8-K33 (26aa) ES pep. K108-K33r (26aa) s S.Š.S.Ss s s -S3 s &s S.S. S S.SS SS S- SSSSS S *Sw& *s SS*s S&S.s S.SSss S. FIG.6C E vess Patent Application Publication Nov. 24, 2016 Sheet 9 of 27 US 2016/0340659 A1 s s Na D O i. i. Patent Application Publication Nov. 24, 2016 Sheet 10 of 27 US 2016/0340659 A1 g Patent Application Publication Nov. 24, 2016 Sheet 11 of 27 US 2016/0340659 A1 ---------------------------- O Sssshi got a sqtaas sessea pooq go aequann y r y ?woudgeø.??goÅeg \76(3)}-} Š&&«$$7-?_{...}}*** N sm $&d??3$*?${{{#x<» ?-----------------------*-----------------------|-----------------------*-----------------------*~~~~--~~~~~~~~~~~~~*- §?z?Ž?Ç t :{}, X x -3 seS$8á pools casquit sesse pooq go equin Patent Application Publication Nov. 24, 2016 Sheet 12 of 27 US 2016/0340659 A1 07 09 (. uu) eunOAJOun. 0 000;~ 000€œ 000?No. 000\_, =3, E 5 © G B ? Patent Application Publication Nov. 24, 2016 Sheet 13 of 27 US 2016/0340659 A1 Patent Application Publication Nov. 24, 2016 Sheet 14 of 27 US 2016/0340659 A1 002X Patent Application Publication Nov. 24, 2016 Sheet 15 of 27 US 2016/0340659 A1 dotx Patent Application Publication Nov. 24, 2016 Sheet 16 of 27 US 2016/0340659 A1 Patent Application Publication Nov. 24, 2016 Sheet 17 of 27 US 2016/0340659 A1 ogzx Patent Application Publication Nov. 24, 2016 Sheet 18 of 27 US 2016/0340659 A1 a. g Patent Application Publication US 2016/0340659 A1 Patent Application Publication US 2016/0340659 A1 Patent Application Publication Nov. 24, 2016 Sheet 21 of 27 US 2016/0340659 A1 i Patent Application Publication Nov. 24, 2016 Sheet 22 of 27 US 2016/0340659 A1 wer N i. Patent Application Publication Nov. 24, 2016 Sheet 23 of 27 US 2016/0340659 A1 Patent Application Publication Nov. 24, 2016 Sheet 24 of 27 US 2016/0340659 A1 i Patent Applicat O Pub ication NOV. 24 , 2016 Sheet 25 Of 27 US 2016/0340659 A1 Patent Application Publication Nov. 24, 2016 Sheet 26 of 27 US 2016/0340659 A1 Patent Application Publication Nov. 24, 2016 Sheet 27 of 27 US 2016/0340659 A1 f s O ii. US 2016/0340659 A1 Nov. 24, 2016 ACTIN BINDING PEPTIDES AND in-vitro, as well as having strong actin-binding properties. COMPOSITIONS COMPRISING SAME FOR None of these properties required the ribonucleolytic activ INHIBITING ANGOGENESIS AND ity of the protein. TREATING MEDICAL CONDITIONS 0007 PCT WO2010/04993 to Shoseyov etal, and Nesiel ASSOCATED WITH SAME nuttman et al (Oncotarget 2014 22:11464-78) (both incor porated herein by reference in their entirety) disclose the FIELD AND BACKGROUND OF THE cloning and efficient expression in bacteria of truncated INVENTION human RNASET2 protein, lacking part of the RNase cata lytic domain, but retaining full tumor Suppressing, anti 0001. The present invention, in some embodiments angiogenic and actin-binding properties. thereof, relates to biologically peptides and, more particu 0008 Conserved domains and structural motifs of T2 larly, but not exclusively, to peptides from T2 RNase having RNase enzymes were investigated by crystallography (Ma actin binding, pharmaceutical compositions comprising the cIntosh, 2011), revealing a general consensus structure com same, therapeutic use thereof and methods for their produc prising 7 C-helices and 8 B-strands, despite the low inter tion. species sequence homology. A complete structural analysis 0002 RNases of the T2 RNase family are single strand of human RNASET2, concurring the structural consensus of specific endoribonucleases acting through base-non-specific the T2 family, has been elucidated (Thorn et al., 2012). nucleolytic cleavage, are broadly distributed throughout all 0009 Kumar et al. (J Mol Model, 2013; 19:613-21) and eukaryotic, plant and animal and also bacterial and viral Gundampati et al (J Mol Model 2012, 18:653-62) using species and are typically characterized by a strongly acidic computer-generated, three dimensional models of A. niger pH optimum for RNase activity. The T2 RNases have RNase B1 and actin in in-silico molecular dynamics docking demonstrated a wide range of biological roles, including simulations, postulated an RNase B1 actin-binding “housekeeping functions, prevention of “self pollination sequence, and proposed that A. niger RNase B1 interaction in plants, antimicrobial defense and tumor Suppression in with cell Surface actin in neoplastic cells could provide a humans. rationale for design of anti-cancer drugs based on RNase B1. 0003 Human RNASET2 is a T-RNase glycoprotein De Leeuw et al (2012), on the basis of three dimensional encoded by the RNASET2 gene which is located on chro conformation and amino acid sequence homology, proposed mosome 6 (6q27) and known as a tumor Suppressor gene two actin binding sites for RNase B1, remote from those (Trubia et al. 1997. Genomics 42:342-344: Acquati et al. postulated by Kumar et al. 2001. Meth Mol Biol 160:87-101). Mutation and loss of 0010 Additional background art includes Nesiel-nutt function of RNASET2 has been associated with increased man et al. Oncoscience 2014, Advanced Publication Nov. tumorigenicity and cancer, including carcinomas of the 26, 2014), Medinger et al (J Angiogenesis Res 2010; 2:10) ovary, breast, uterus, stomach, liver, colon/rectum, kidney and Rosca et al. (Curr. Res Biotech, 2011: 12:1101). and hematologic malignancies, such as non-Hodgkin, B-cell lymphoma and acute lymphoblastic leukemia. SUMMARY OF THE INVENTION 0004 Acquati et al. (PNAS 2011, PNAS 2013) have shown that overexpression of human RNASET2 can sup 0011. According to an aspect of some embodiments of press growth of ovarian and other cancerous tumors in the present invention there is provided an isolated peptide in-vivo experiments, independently of its ribonucleolytic comprising a core amino acid sequence which comprises at least 10 amino acids of helix 5 of human RNASET2, or activity, although no Such anti-tumorigenic activity was naturally occurring homologues thereof, or conservative observed in the transformed cells in-vitro (Acquati et al. substitutions thereof, wherein the peptide is 23-50 amino 2011 and Liu et al., 2002). acids in length and wherein the peptide binds actin. 0005. In PCT WO 2001/15531 (incorporated herein by 0012. According to an aspect of some embodiments of reference in its entirety), the present inventors have shown the present invention there is provided a composition of that recombinant B1 T2 RNase from A. niger can inhibit matter comprising the isolated peptide of the invention in-vitro tumor growth, tumorigenesis metastatic transforma formulated with a cell penetrating agent. tion and metastatic spread in-vivo, and effectively bind actin in both cell-free systems and on the surface of cancer cells 0013. According to an aspect of some embodiments of in culture. Further investigation revealed in-vitro inhibition the present invention there is provided a composition of by A. niger RNase B1 of angiogenesis, inhibition of cell matter comprising the isolated peptide of the invention extension and cell migration in cancer cells and endothelial formulated with a targeting moiety. cells, and in-vivo inhibition of tumor angiogenesis meta 0014. According to some embodiments of the invention static transformation and metastatic spread, in a variety of the cell penetrating agent comprises a cell penetrating pep cancer cell lines, and actin binding activity on Western blots tide covalently attached to the peptide. (see U.S. Pat. Nos. 7,811,981 and 8,236,543, incorporated 0015.
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