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Wo 2007/101227 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 7 September 2007 (07.09.2007) PCT WO 2007/101227 A2 (51) International Patent Classification: Not classified 85284 (US). LAKE, Doug [US/US]; 3930 E. Fox Cr., Mesa, AZ 85205 (US). (21) International Application Number: PCT/US2007/062920 (74) Agents: SPRATT, Gwendolyn, D. et al.; Needle & Rosen berg, P.c, Suite 1000, 999 Peachtree Street, Atlanta, GA (22) International Filing Date: 30309-3915 (US). 27 February 2007 (27.02.2007) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, (26) Publication Language: English CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FT, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, (30) Priority Data: JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, 60/777,534 27 February 2006 (27.02.2006) US LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (71) Applicant (for all designated States except US): ARI¬ RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, ZONA BOARD OF REGENTS FOR AND ON BE¬ TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW HALF OF ARIZONA STATE UNIVERSITY [US/US]; 699 South Mill Avenue, Suite 601, Tempe, AZ 85281 (84) Designated States (unless otherwise indicated, for every (US). kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (72) Inventors; and ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (75) Inventors/Applicants (for US only): JOHNSTON, European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, Stephen, A. [US/US]; 8606 S. Dorsey Ln, Tempe, AZ FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, [Continued on next page] (54) Title: IDENTIFICATION AND USE OF NOVOPEPTIDES FOR THE TREATMENT OF CANCER (57) Abstract: Disclosed are compositions relating to novopeptides identified by the presence of frameshift mutations in tumor genes previously not identified as being oncogenic. The disclosed peptides can be used in the disclosed methods for the treatment of cancer. 1 2 3 4 5 6 7 8 9 10 M RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, For two-letter codes and other abbreviations, refer to the "Guid- GN, GQ, GW, ML, MR, NE, SN, TD, TG). ance Notes on Codes and Abbreviations" appearing at the begin- Published ning of each regular issue of the PCT Gazette. — without international search report and to be republished upon receipt of that report IDENTIFICATION AND USE OF NOVOPEPTIDES FOR THE TREATMENT OF CANCER 1. This application claims the benefit of U.S. Provisional Application No. 60/777,534, filed on February 27, 2006, which is incorporated herein by reference in its entirety. I . BACKGROUND 2. It is estimated that in 2004 more than 2.4 million new cancer cases will be diagnosed in the U.S. and more than 1 million are expected to be skin cancers. Of those individuals with skin cancer, -96,000 will be diagnosed with melanoma (4% of newly diagnosed cancers), the most deadly form of skin cancer. Furthermore, the incidence of melanoma continues to increase faster than any other cancer. The stochastic nature of 90 to 95% of all cancers means that everyone is at risk of developing a cancer hi the United States, men have a 50% lifetime risk of developing cancer, while women have a 33% chance (ACS, 2004). With an annual mortality rate of -563,700 per year, cancer is the second leading cause of death in the U.S. 3. Vaccination against cancer has been proposed for treatment, and occasionally prevention, of cancer, and considerable research effort has been devoted to the exploration of a variety of cancer vaccination strategies. The goal of finding vaccine compositions and treatment methods that are capable of reliably and predictably overcoming tolerance and setting in motion an immune response against tumor cells without inducing autoimmunity has, until now, proved elusive. It is nevertheless clear that cancerous cells express proteins that can be recognized by the immune system, as demonstrated by experiments in which mice vaccinated with various kinds of tumor cell preparations show protection from tumor challenge. Antigens that are expressed in or by tumor cells are referred to as "tumor associated antigens" ("TAA' s"). A particular TAA may or may not also be expressed in non-cancerous cells; TAA' s that are not expressed or rarely expressed in non-cancerous cells, or whose expression in non-cancerous cells is sufficiently reduced in comparison to that in cancerous cells that an immune response induced upon vaccination is reasonably specific to cancerous cells, are referred to as "tumor specific antigens" ("TSA' s"). 4. Over the past two decades, many labs have devised numerous techniques which aim to turn the patient's immune system against a pre-existing tumor (Berzofsky et al., 2004). These include the use of whole cells, peptides, genetically modified tumor cells, heat-shock proteins or apoptotic tumor cells to stimulate the host's immune system to respond to antigens that are characteristic of cancer cells. Arguably the most elegant approach to cancer vaccination is to use vaccine formulations composed of known and defined TAA's, since this will maximize specificity. Functionally, TAA's may be classed as self and non-self. Self TAA's are derived from nonmutated genes whose expression is limited to selected normal tissues or to overexpressed proteins. While most TAA's identified to date belong to this self class, there are two large potential problems associated with such antigens: autoimmunity and tolerance. Non-self TAA's are expressed exclusively by cancer cells, and can be thought of as tumor-specific antigens (TSA' s). TSA' s can originate either exogenously (such as those derived from viral proteins in virally- associated tumors) or endogenously. Mutation-derived TSA's can arise from point mutations, translocations, and exon mis-splicing. Unlike self TAA's, TSA's do not pose the risk of autoimmunity and tolerance. II. SUMMARY 5. Disclosed are methods for identifying and immunologically screening candidate antigens for inclusion in a prophylactic and/or therapeutic cancer vaccine. Further disclosed is a general class of antigens, referred to herein as novopeptides, as well as two specific subsets thereof, non-MS novopeptides and FS-novopeptides. Disclosed are methods and compositions related to novopeptides, unique nonsense proteins specific to a tumor, for use in diagnosing, preventing and treating cancer. Also disclosed is a method of using novopeptides to induce an immune response against cancer. Disclosed are vaccines having one or more novopeptide components, which are used prophylactically, or as a therapeutic treatment against existing cancerous cells. III. BRIEF DESCRIPTION OF THE DRAWINGS 6. The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description illustrate the disclosed compositions and methods. 7. Figure 1 demonstrates a method of determining frameshift frequency in tumor cells using a mouse melanoma model Bl 6F10. A. cDNA was generated RNA from cultured cells. It was sequenced directly by RT-PCR sequencing. B. In vivo confirmation of in vitro-derived FS mutations. To confirm that the FS was expressed in vivo, RNA was extracted from B16 lung metastases after injection of cells systemically. cDNA was generated and the FS confirmed by RT-PCR sequencing. 8. Figures 2a and 2b show PCR amplification of FS1-78 and FS6-21, respectively. Arrow indicates FS band; other bands are wild type alleles. Lane 1: B16/F1 tumor cells; Lane 2: B16/F10 tumor cells; Lane 3: normal heart; Lane 4: normal intestine; Lane 5: normal kidney; Lane 6: normal liver; Lane 7: normal lung; Lane 8: normal skeletal muscle; Lane 9: normal skin; Lane 10: normal spleen; Lane M: Molecular weight marker. 9. Figure 3 shows the linear expression element construction (LEE). Each LEE is comprised of a fragment that contains a mammalian promoter (blue), the ubiquitin gene for better intracellular processing (yellow), a fragment that contains transcriptional and translational terminators (red). The two fragments are linked via the frameshift sequence (green). 10. Figure 4 shows prophylactic immunization of C57B6 mice with FS 1-78 neopeptide delays B16F10 tumor growth. C57B6 mice were immunized with the increasing amounts of LEE expressing FS 1-78 peptide and l µg of pGM-CSF. After a primary immunization mice were boosted 2 weeks later. One week after the boost, mice were challenged on day zero (arrow) with 1 x 105 Bl 6F10 melanoma tumor cells. 11. Figure 5 shows prophylactic immunization of Balb/c mice with FS 1-78 neopeptide delays 4Tl tumor growth. Balb/c mice were immunized with 3.2ng of FS 1-78 LEE + lug of pGM-CSF and boosted with the same gene vaccine after 2 weeks. One week after the boost, mice were challenged with 5 x 104 4Tl breast tumor cells. Seventeen days after 4Tl challenge, tumors started to grow. Control is pGM-CSF plasmid alone. 6-21-Mut is another frameshift not found in 4Tl tumors. 12. Figure 6 shows the survival curve in response to prophylactic vaccination with frameshift peptide-encoding genetic vaccines. On Day -8, mice were immunized with the FS6-21mut peptide sequence (squares), the FSl-78mut peptide sequences (crosses), a combination of both (triangles), or an irrelevant peptide sequence (diamonds).
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