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(12) United States Patent (10) Patent No.: US 9,345,770 B2 Storkus Et Al

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(12) United States Patent (10) Patent No.: US 9,345,770 B2 Storkus Et Al US00934,577OB2 (12) United States Patent (10) Patent No.: US 9,345,770 B2 Storkus et al. (45) Date of Patent: May 24, 2016 (54) MMUNOGENIC TUMIOR ASSOCATED (2013.01); G0IN33/57438 (2013.01); G0IN STROMAL CELLANTIGEN PEPTIDES AND 33/57446 (2013.01); A61 K 2039/5154 METHODS OF THEIR USE (2013.01); A61 K 2039/5 158 (2013.01); A61 K 2039/5256 (2013.01); A61 K 2039/53 (2013.01); (71) Applicant: University of Pittsburgh-Of the A61 K 2039/55538 (2013.01) Commonwealth System of Higher (58) Field of Classification Search Education, Pittsburgh, PA (US) None (72) Inventors: Walter J. Storkus, Pittsburgh, PA (US); See application file for complete search history. Anamika Bose, Kolkata (IN); Jennifer Lynn Taylor, McDonald, PA (US); Xi (56) References Cited Zhao, Pittsburgh, PA (US); Devin B. U.S. PATENT DOCUMENTS Lowe, Pittsburgh, PA (US) 7,981,424 B2 7/2011 Malli et al. (73) Assignee: University of Pittsburgh-Of the 2009,0299038 A1 12/2009 Nakamura et al. Commonwealth System of Higher Education, Pittsburgh, PA (US) FOREIGN PATENT DOCUMENTS AU 2003218603 B2 10, 2003 (*) Notice: Subject to any disclaimer, the term of this AU 2007318483 A1 5, 2008 patent is extended or adjusted under 35 WO WO995.5865 * 11/1999 U.S.C. 154(b) by 0 days. WO WOO3,O75921 A2 9, 2003 WO WOO3O86450 * 10/2003 Appl. No.: 14/358,705 (21) OTHER PUBLICATIONS (22) PCT Fled: Nov. 15, 2012 Zhao et al. Molecular therapy 19:805-814, Apr. 2011.* PCT NO.: PCT/US2012/065.327 Gonzalez et al., Eur J. Immunol 45:2615-27, 2015.* (86) International Search Report from parent PCT Application No. PCT/ S371 (c)(1), US2012/065327, 7 pages (mailed Dec. 19, 2012). (2) Date: May 15, 2014 Written Opinion from parent PCT Application No. PCT/US2012/ 065327, 6 pages. (mailed Dec. 19, 2012). (87) PCT Pub. No.: WO2O13/07482O Yan et al., “RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease.” Nature 22:382(6593):685-691 (1996) PCT Pub. Date: May 23, 2013 (Abstract only). Zhao et al., “Intratumoral IL-12 Gene Therapy Results in the (65) Prior Publication Data Crosspriming of Tcl Cells Reactive Against Tumor-associated US 2014/0314758A1 Oct. 23, 2014 Stromal Antigens.” Mol Ther: 19(4):805-814 (2011). Related U.S. Application Data * cited by examiner (60) Provisional application No. 61/560,597, filed on Nov. Primary Examiner — Lei Yao 16, 2011. (74) Attorney, Agent, or Firm — Klarduist Sparkman, LLP (51) Int. C. (57) ABSTRACT A6 IK 45/06 (2006.01) A6 IK38/08 (2006.01) Immunogenic peptides from tumor associated Stromal cell A6 IK38/17 (2006.01) antigens, including combinations of Such peptides, are dis GOIN33/574 (2006.01) closed herein. In some examples the peptides are useful for A6 IK39/00 (2006.01) methods of eliciting an immune response. In additional A6 IK3I/506 (2006.01) examples the peptides are useful for methods of treating (52) U.S. C. cancer. Methods for decreasing vascularization of a tumor CPC ............... A61K 45/06 (2013.01); A61 K3I/506 using a Protein Delta Homolog 1 (DLK1) protein or a nucleic (2013.01); A61 K38/08 (2013.01); A61 K acid encoding the protein are also disclosed. 38/1709 (2013.01); A61K39/00II (2013.01); G0IN33/574 (2013.01); G0IN33/5743 17 Claims, 27 Drawing Sheets U.S. Patent May 24, 2016 Sheet 1 of 27 US 9,345,770 B2 FIG . 1A U.S. Patent May 24, 2016 Sheet 2 of 27 US 9,345,770 B2 FIG. 1B -- yf Sri s gp OO 3-Actin U.S. Patent May 24, 2016 Sheet 3 of 27 US 9,345,770 B2 FIG. 2A FIG 2B KC U.S. Patent May 24, 2016 Sheet 4 of 27 US 9,345,770 B2 see wwii-, 8.8 X, (8S is (&x. exist So M \s: $ (Odd & is). A S. ..i. s S sS. SSS)Kas w d w w Sei (168) qu-bold (9ev) adhn $ Š S&SN. xxxiY. \s W. w.x. 8:8- &- x -S. (888 i &isiN &. (88w ex ( & & ex Š 88 &Y is (sae ixi to St. Xix (9a) >ic {{ { a \si U.S. Patent May 24, 2016 Sheet 6 of 27 US 9,345,770 B2 FIG. 4 U.S. Patent May 24, 2016 Sheet 7 Of 27 US 9,345,770 B2 FIG. 5 ·luww+z?l 21|oo!d6+ w & tes stiniated wit: U.S. Patent US 9,345,770 B2 U.S. Patent May 24, 2016 Sheet 9 Of 27 US 9,345,770 B2 FIG. 7 600 prior. Control Ni (k 500 & g-A-A2 Š -C 400 380 200 it? ( 600 p.mmm, D.C. 5-Treated St - 3 - it t g g : s Se a e o Pericytes WEC Target Cells Analyzed: U.S. Patent May 24, 2016 Sheet 10 of 27 US 9,345,770 B2 áæta?Y 88" 8GIO U.S. Patent May 24, 2016 Sheet 11 of 27 US 9,345,770 B2 FIG. 9A FIG. 9B ?!--~~~~~~~~ **** av's est-user ineculation U.S. Patent May 24, 2016 Sheet 12 of 27 US 9,345,770 B2 FIG. 10A FIG. 10B p 8. 3 - 3 &tive *egitie: FIG. 10C FIG. 10D +****???Å E is Y-se: Peptide: U.S. Patent May 24, 2016 Sheet 13 Of 27 US 9,345,770 B2 FIG. 11A soooooooo- sex sex weexs Control Vaccine XS steeise Vareiaei ww {{s- acD8 g" s w rf Days Post-Tunner Inoculation F.G. 11B 8. r arrassarass- SSSSSS &n. Naas S. Sassarasara-arss i it : ) it : Pays Post-funer inoculation F.G. 11C -- c. 388: - - E38: {}ay s trar $8; Se ER3 ... '8: Si:SS is -x-- $8: SE&SS * k -- Ss. VES: ----&- A&; ERS 83 8: S: S8 is SS s: says east-Tirner are ulation U.S. Patent May 24, 2016 Sheet 14 of 27 US 9,345,770 B2 FIG. 12 a 20 1000 80 38 8 .ssori:****P****,ano?ovAxridi?a?wpoova Hae??z?***3: K K ?vi.xså Hae?.******** serieyte W ************ ±(+-******** T2 - TBVA-Berived Peptides: U.S. Patent May 24, 2016 Sheet 15 Of 27 US 9,345,770 B2 200 too a Sa. W . 4ee p.m. 300 288 it}} a : 400 300 288 100 : Nome faaaaaaaaaaaaaaa- 3 S S. ( S) { Si S ( S) bays Past- unior acetiation U.S. Patent May 24, 2016 Sheet 16 of 27 US 9,345,770 B2 FIG. 14 R8. U.S. Patent May 24, 2016 Sheet 17 Of 27 US 9,345,770 B2 FIG. 15 K Eph A2 HBB NR PDGFRB SY RESS EY YER YEGFR. (3. -Actin U.S. Patent May 24, 2016 Sheet 18 of 27 US 9,345,770 B2 5 w Xa Y. N. NoN. s $ N N. N s& 8 isssssssssssssssssssssssssssssssss CDs TIL 8 & 38(YS SS: 38 S8 & Sis 88 R Sax w ar. 0.56 & is $$$. ii & 8& is 38 & & Si: 888 C)S. (8 8 : S8 3 & Trai Size is: U.S. Patent Sheet 19 Of 27 US 9,345,770 B2 F.G. 17A FIG 17B 34% ;-- st -- 'etirie U.S. Patent May 24, 2016 Sheet 20 Of 27 US 9,345,770 B2 FIG. 18 DC + Peptide w U.S. Patent May 24, 2016 Sheet 21 of 27 US 9,345,770 B2 U.S. Patent May 24, 2016 Sheet 22 of 27 US 9,345,770 B2 *OCI |001 |08 |09 |ow 83u83S8ion pee ifieu U.S. Patent May 24, 2016 Sheet 23 of 27 US 9,345,770 B2 - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - a mama arrananar exaaaaaa. wa My S > xx is so a key v. t N w s s w- N w w c as 80x) a2ueoSa ionid to e2e30 L (six eauss&ion six 83u83 saion p3e333 -oo auaouad pee ifieu 8do p33e389 it yid N AWOACO 2 i e ce s N w (guiu) aziS WON U.S. Patent May 24, 2016 Sheet 24 of 27 US 9,345,770 B2 ; ei SS. 38'N, (x) aguaose ionid fii (Ofgh fiti pae fest SN wn Na w C U.S. Patent May 24, 2016 Sheet 25 Of 27 US 9,345,770 B2 FIG. 23A . S , IvNEG IvDLK1 U.S. Patent May 24, 2016 Sheet 26 of 27 US 9,345,770 B2 U.S. Patent May 24 9 2016 Sheet 27 Of 27 US 9,345,770 B2 US 9,345,770 B2 1. 2 IMMUNOGENIC TUMIOR ASSOCATED In further embodiments, the immunogenic TASA peptides, STROMAL CELLANTIGEN PEPTIDES AND polynucleotides, vectors and host cells can be used, for METHODS OF THEIR USE example, for inducing an immune response to one or more TASA or to treat or inhibit cancer. This is the U.S. National Stage of International Application In additional embodiments, methods are disclosed for No. PCT/US2012/065327, filed Nov. 15, 2012, which was treating a tumor, such as by decreasing vascularization of a published in English under PCT Article 21(2), which in turn tumor. The methods include administering to a subject having claims the benefit of U.S. Provisional Application No. a tumor an effective amount of a Protein Delta Homolog 1 61/560,597, filed on Nov. 16, 2011, which is incorporated by (DLK1) protein, a nucleic acid encoding the DLK1 protein, reference herein in its entirety. 10 or a dendritic cell transformed with the nucleic acid. In some non-limiting examples, the methods also include administer ACKNOWLEDGMENT OF GOVERNMENT ing to the subject a therapeutically effective amount of beva SUPPORT cizumab, Sunitinib, axitinib, an HSP90 inhibitor, or gencitab ine/fludarabine. In additional non-limiting examples, the This invention was made with government Support under 15 tumor is a melanoma, hepatocellular carcinoma or colorectal Grant Nos.
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