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(12) Patent Application Publication (10) Pub. No.: US 2016/0324897 A1 INGBER Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0324897 A1 INGBER Et Al US 20160324897A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0324897 A1 INGBER et al. (43) Pub. Date: Nov. 10, 2016 (54) PLATELET DECOYS AND USE THEREOF Related U.S. Application Data (60) Provisional application No. 61/928,458, filed on Jan. (71) Applicant: PRESIDENT AND FELLOWS OF 17, 2014, provisional application No. 61/938,329, HARVARD COLLEGE, Cambridge, filed on Feb. 11, 2014. MA (US) Publication Classification (72) Inventors: Donald E. INGBER, Boston, MA (US); Anne-Laure PAPA, Boston, MA (51) Int. Cl. (US) A 6LX 35/9 (2006.01) CI2N 5/078 (2006.01) (52) U.S. Cl. (73) Assignee: PRESIDENT AND FELLOWS OF CPC ............. A61K 35/19 (2013.01); C12N5/0644 HARVARD COLLEGE, Cambridge, (2013.01) MA (US) (57) ABSTRACT (21) Appl. No.: 15/111.999 The invention provides platelet decoys and mimics that can bind to platelet receptor substrate but do not undergo platelet (22) PCT Filed: Jan. 16, 2015 activation. The invention also provides methods of using the platelet decoys for treating, preventing or inhibiting a dis (86) PCT No.: PCT/US 15/11805 ease or disorder in Subject when platelet activation, aggre S 371 (c)(1), gation and/or adhesion contributes to the pathology or (2) Date: Jul. 15, 2016 symptomology of the disease. Patent Application Publication Nov. 10, 2016 Sheet 1 of 13 US 2016/0324897 A1 """ FC a C E -aos FIG. I.A. A. 1828 15. s ar st s: -- as X A. i "f '" C ... C. E. P.C..re- -...-FC CSF--...-kee. FIG. IC FIG. I. Patent Application Publication Nov. 10, 2016 Sheet 2 of 13 US 2016/0324897 A1 C. R 1'- 1, lo' of. is to is 16... 10 o' errorisri erreror 1. 2 3 4 5 F- - a C C, EP-ase al-Fi C.E. P. ae : iii. ! 1" toy. 33 to of . is to is to 10' 10' T i T "" ". ". "" FC E-i o-FCE PC--see - CAE PC--is. FIG. I.G FIG. I. Patent Application Publication Nov. 10, 2016 Sheet 3 of 13 US 2016/0324897 A1 E 2 O i. (N Ss R QS x R avoids iNY s YXX XXX u?ic Namoo Sri Osday NiOS d'hi as ele is as as ele sts as a was a % Patent Application Publication Nov. 10, 2016 Sheet 4 of 13 US 2016/0324897 A1 ES ar s s ww. s 3. SAE xen ng . s w ado sw s c3 s s: "3" is w isesi CAER CE RESEC NES (a.i. CACER CEERESEC ENS (a.i. w FIG 3A s s bi SEED is SAE 16 5 18-- 5 to 1 Trrrrt Fre." re-re rTrE Trily Trily in CANCER CEL FLORESCENCE INTENSITY (a.i.) ACFE ECANGER CELL FLORESCENCENTENSTY (a.i.) Y-y-/ FIG. 3B Patent Application Publication Nov. 10, 2016 Sheet 5 of 13 US 2016/0324897 A1 -8-3 C SAE i CACER CE. RESENCE ESY (a, CCER CE, FRESENCEESY (3...) Y-y-/ FIG. 3C i SE t SE CBCE E RESEC NESY (i. CAER CE, FRESECE ENSY 3...) Y-y-/ FIG. 3 Patent Application Publication Nov. 10, 2016 Sheet 6 of 13 US 2016/0324897 A1 ii-V-3 R8-3 PAES i CER CE, FRESEE ES 3. ACER CE, FRESECE SY., FIG. 3E FIG, 3F s C. s CF.; e PES of s : 's e.g. E. s s kin kn e s w arw xss sd E. CAER CE. FORESCENE ENSY 3,...} as CANCER CE, FRESCECE ESY 3., FIG, 3G FIG. 3, Patent Application Publication Nov. 10, 2016 Sheet 9 of 13 US 2016/0324897 A1 CE-E PE S S S S I PAS, CE (MADPIN PASMA parts toys plates its patters its is it FIG. 5, Patent Application Publication Nov. 10, 2016 Sheet 10 of 13 US 2016/0324897 A1 3-E PE CR ADP (58: A) S X Š & S S SS yS SŠ S S & S y FBRG parts is pairs plays parts Eys ii Patent Application Publication Nov. 10, 2016 Sheet 11 of 13 US 2016/0324897 A1 is is x is is s w s s as: \xS eas e * & -- the Y ce s & & S : E s E.xxxx Š.s . te is ex: ex s & " . S SS w asS is irra w is wnex ass ge s & Sas ex is sis ex s s wark esAn is st s sma is i es s new are arr al sa . 3 oilo r s& is as ess is is Patent Application Publication Nov. 10, 2016 Sheet 12 of 13 US 2016/0324897 A1 S. S Š s s x xxx ww. & SSS S S Si S. Patent Application Publication Nov. 10, 2016 Sheet 13 of 13 US 2016/0324897 A1 sets s: ?eee????????????******?x;{{! Sid US 2016/0324897 A1 Nov. 10, 2016 PLATELET DECOYS AND USE THEREOF and ARDS (Bachofen M, Weibel E. R. Structural alterations of lung parenchyma in the adult respiratory distress Syn RELATED APPLICATIONS drome. Clin Chest Med. 1982; 3(1):35-56. Epub 1982 Jan. 0001. This application claims benefit under 35 U.S.C. 1. PubMed PMID: 7075161). New evidence also suggests S119(e) of the U.S. Provisional Application No. 61/928,458, that aspirin has a role in preventing recurrent DVT (Becattini filed Jan. 17, 2014, and No. 61/938,329, filed Feb. 11, 2014, C, Agnelli G. Schenone A, Eichinger S. Bucherini E. Silin the content of both of which is incorporated herein by gardi M. et al. Aspirin for preventing the recurrence of reference in their entirety. venous thromboembolism. N Engl J Med. 2012; 366(21): 1959-67. Epub 2012 May 25, doi: 10.1056/NEJ TECHNICAL FIELD Moa1114238. PubMed PMID: 22621626), this could be due to its inhibition of platelets. 0002 The present disclosure relates generally to platelet decoys and mimics and methods of making and using same. 0004 Metastatic dissemination of the primary tumor is one of the main causes of death in cancer patients (H. B. P. Pearson, N. In Metastatic Cancer. Integrated Organ System BACKGROUND and Biological Approach, Landes Bioscience ed.: Jandial, R. 0003 Increased number of platelets is seen in cancer, H. K., Ed. 2012). Since several decades, evidence has been myeloproliferative diseases and in chronic inflammatory accumulating that platelets play a crucial role in the meta conditions (Schafer A I. Thrombocytosis. N Engl J Med. static cascade. Indeed, their support in regard to Circulating 2004; 350(12): 1211-9. Epub 2004 Mar. 19. doi:10.1056/ Tumor Cells (CTCs) is multifold: (i) shielding CTCs from NEJMra035363. PubMed PMID: 15028825). This culmi shear stress in the bloodstream, (ii) protecting CTCs from nates with a strong possibility for these patients to develop the immune system, (iii) adhering to the endothelial wall So thrombosis. An increased activation of platelets plays an as to arrest CTCs within the vasculature, thus promoting important role in the pathogenesis of several diseases; this new sites of metastasis and (iv) providing CTCs with includes disseminated intravascular coagulation (DIC) (Levi pro-oncogenic and angiogenic factors that they release (N. M. van der Poll T. Disseminated intravascular coagulation: M. Bambace, C. E. Holmes, The platelet contribution to a review for the internist. Intern Emerg Med. 2013; 8(1): cancer progression. J Thromb Haemost 9, 237-249 (2011): 23-32. Epub 2012 Sep. 28. doi:10.1007/s11739-012-0859 L. J. Gay, B. Felding-Habermann, Contribution of platelets 9. PubMed PMID: 23015284), sepsis (Li Z. Yang F, Dunn S, to tumour metastasis. Nat Rev Cancer 11, 123-134 (2011): Gross A K, Smyth SS. Platelets as immune mediators: their and G. L. Klement, T. T. Yip, F. Cassiola, L. Kikuchi, D. role in host defense responses and sepsis. Thromb Res. Cervi, V. Podust, J. E. Italiano, E. Wheatley, A. Abou-Slaybi, 2011; 127(3):184-8. Epub 2010 Nov. 16. doi: 10.1016/j. E. Bender, N. Almog, M. W. Kieran, J. Folkman, Platelets thromres.2010.10.010. PubMed PMID: 21075430; PubMed actively sequester angiogenesis regulators. Blood 113, 2835 Central PMCID: PMC3042496) and heparin-induced throm 2842 (2009)). Additionally, significantly high platelet counts bocytopenia (HIT) (Warkentin T E. Heparin-induced throm (thrombocytosis) are found in 10 to 57% of cancer patients bocytopenia: pathogenesis and management. BrJ Haematol. (E. Sierko, M. Z. Wojtukiewicz, Inhibition of platelet func 2003: 121(4):535-55. Epub 2003 May 20. PubMed PMID: tion: does it offer a chance of better cancer progression 12752095). DIC is a pathology leading to generalized acti control? Semin Thromb Hemost 33, 712-721 (2007)), and Vation of platelets and the coagulation cascade. This results are associated with poor prognosis (R. L. Stone, A. M. Nick, in the formation of microvascular clots and a resultant I. A. McNeish, F. Balkwill, H. D. Han, J. Bottsford-Miller, excessive consumption of platelets and coagulation proteins. R. Rupairmoole, G. N. Armaiz-Pena, C. V. Pecot, J. Coward, It is often a complication of preexisting indications such as M. T. Deavers, H. G. Vasquez, D. Urbauer, C. N. Landen, W. sepsis (Semeraro N. Ammollo CT. Semeraro F. Colucci M. Hu, H. Gershenson, K. Matsuo, M. M. Shahzad, E. R. King, Sepsis, thrombosis and organ dysfunction. Thromb Res. I. Tekedereli, B. Ozpolat, E. H. Ahn, V. K. Bond, R. Wang, 2012; 129(3):290-5. Epub 2011 Nov. 9... doi: 10.1016/j. A. F. Drew, F. Gushiken, D. Lamkin, K. Collins, K. thromres. 0.2011.10.013. PubMed PMID: 22061311), pull DeGeest, S. K. Lutgendorf, W. Chiu, G. Lopez-Berestein, V. monary embolism (Levi M. Disseminated intravascular Afshar-Kharghan, A. K. Sood, Paraneoplastic thrombocyto coagulation or extended intravascular coagulation in mas sis in ovarian cancer.
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