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(12) Patent Application Publication (10) Pub. No.: US 2016/0299145 A1 Love Et Al US 2016O299145A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0299145 A1 LOVe et al. (43) Pub. Date: Oct. 13, 2016 (54) METHODS AND KITS FOR DETECTING (60) Provisional application No. 60/865,621, filed on Nov. PROSTATE CANCER BOMARKERS 13, 2006. (71) Applicant: Life Technologies Corporation, Publication Classification Carlsbad, CA (US) (51) Int. Cl. (72) Inventors: Bradley Love, Timonium, MD (US); GOIN 33/574 (2006.01) Jeffrey Rogers, Escondido, CA (US); GOIN 33/564 (2006.01) Joseph Beechem, Eugene, OR (US); (52) U.S. Cl. Lilin Wang, San Diego, CA (US) CPC. G0IN 33/57434 (2013.01); C12Y 207/11001 (2013.01); C12Y 207/10001 (2013.01); G0IN (21) Appl. No.: 15/132,821 33/564 (2013.01); G0IN 2333/91205 (2013.01) (22) Filed: Apr. 19, 2016 (57) ABSTRACT Related U.S. Application Data Provided herein are novel autoantibody biomarkers, and (63) Continuation of application No. 13/308.930, filed on panels for detecting autoantibody biomarkers for prostate Dec. 1, 2011, now abandoned, which is a continuation cancer, and methods and kits for detecting these biomarkers of application No. 11/939,484, filed on Nov. 13, 2007, in the serum of individuals Suspected of having prostate now abandoned. CaCC. 3 captise at 3ies woxosomeowox 3. auto-airtigens xxaasaxxaasaxxas axxas axia ?axat Xaxa: ax Moise Anti-hina k, 3 step Positive control) Morisa Anti-hiurnar g(3, 3 step Positive Control) Frfeit i. 3 Ste: Positive Cofiro ... Goat Anti-ta g3, 3 step. Positive Control) Hanan g3, 4 step (Positive Conto) -----Y Patent Application Publication Oct. 13, 2016 Sheet 1 of 9 US 2016/02991.45 A1 8 at are attades 8 aut-aftigens V WaaSXXA8338 house Anti-taaf k, 3 step {Positive control) kiose Ati-hit smarigg, 3 step Positive Control) Pote: i. 3s sieg Positive Citrol) ..." Goat Art-Hanan iggs, 3 step (Positive Control) it has g3, 4 Ste: Psitive Contro six-sex FGURE Patent Application Publication Oct. 13, 2016 Sheet 2 of 9 US 2016/02991.45 A1 FIGURE 2A Patent Application Publication Oct. 13, 2016 Sheet 3 of 9 US 2016/02991.45 A1 FIGURE 2B Patent Application Publication Oct. 13, 2016 Sheet 4 of 9 US 2016/02991.45 A1 KR kinase domai competitio {{ {~-c.c.; 3. 88: 4000 2 . - 3 38 . 4: coacetation of KOR gia Capetities experiest with recois a P Stein s X !--w. 1555 . a-a-aa-aa-a-a-a-a-a-a-a-a-Maaaaaaa Patent Application Publication Oct. 13, 2016 Sheet 5 of 9 US 2016/02991.45 A1 Patent Application Publication Oct. 13, 2016 Sheet 6 of 9 US 2016/02991.45 A1 Patent Application Publication Oct. 13, 2016 Sheet 7 of 9 US 2016/02991.45 A1 KR ar. V. 0.9 | 0.8 0.7 0.6 0.5 .4 f 3 pSA ?: PSA, AJC is 5598 O. to KDR, AJC - 8086 (O. - PV-1 AUC is 75 Y KDR and PM-1 AUC = 9268 : i : & O O. O.2 C3 O.4 O.5 C.6 O.7 O.8 O.9 False Positive Rate (1 - Sensitivity) FIGURE 3C Patent Application Publication Oct. 13, 2016 Sheet 8 of 9 US 2016/02991.45 A1 KR PV1 CA B FIGURE 4 Patent Application Publication Oct. 13, 2016 Sheet 9 of 9 US 2016/02991.45 A1 he Sangie The Chip he 33 he Caitation Discovery of harkers Postate selective for Ca over 3 Cance Patient xia. Sertar asna u. 3. &XSS& Patie Disease OC Sed Sr. iagnostic Chip The Discovery Pasa *: ( ...} Catabase inig and literatife search Genetic pathway of prostate inorigeriesis Cell free expression of tinor antigens Faification of protei arrays FIGURE 5 US 2016/02991.45 A1 Oct. 13, 2016 METHODS AND KITS FOR DETECTING 0007 Another condition known as prostate intraepithelial PROSTATE CANCER BOMARKERS neoplasia (PIN) may precede prostate cancer by five to ten years, but requires no treatment or intervention. Currently CROSS REFERENCE TO RELATED there are no specific diagnostic tests for PIN, although the APPLICATIONS ability to detect and monitor the potentially pre-cancerous condition would contribute to early detection and enhanced 0001. This application is a continuation of U.S. patent Survival rates for prostate cancer. application Ser. No. 13/308.930, filed Dec. 1, 2011, now 0008 Autoantibody-based approaches using protein abandoned, which is a continuation of U.S. patent applica microarrays have a number of distinct advantages for the tion Ser. No. 11/939,484, filed Nov. 13, 2007, now aban discovery of quality diagnostic biomarkers. Many of the doned, which claims priority to U.S. Provisional Application potentially best disease-based biomarkers are not secreted No. 60/865,621, filed Nov. 13, 2006, which disclosures are into the blood at levels that are detectable in a robust manner. herein incorporated by reference in their entirety. Such biomarkers will always be “unavailable' for conve 0002 The specification incorporates by reference the nient in-vitro blood-based diagnostic tests. However, Sequence Listing filed herewith named “April-19-2016 autoantibodies to these same specific non-secreted biomark Cont-Sequence-Listing..txt created Apr. 19, 2016 and hav ers (if formed), will circulate beyond the boundaries of the ing a size of 36,808 bytes. diseased tissue and will be stable in whole-blood for extended periods of time. Using a protein array approach BACKGROUND one can very quickly explore of a large number of potential 0003. The invention generally relates to biomarkers asso protein targets for the presence of autoantibodies to correlate ciated with prostate cancer, and methods and compositions with specific diseases. for the detection, diagnosis, prognosis, and monitoring of 0009 Cancer initiation and progression has been shown the progression of prostate cancer. to associate with the process of immunoediting (Dunn et al. 0004 Prostate cancer (also referred to herein as “PCa) is (2004), “The three Es of cancer immunoediting.” Annu Rev the most prevalent form of cancer and the second most Immunol. 22:329-60). In immunoediting, the immune sys common cause of cancer death in American men (Jemal et tem interacts with cancer and induces a cancer specific al. (2007) “Cancer statistics.” CA Cancer J Clin. 57(1):43 immune response, with unique immune signatures charac 66). When prostate cancer is diagnosed in its early stages, teristic of the various stages of cancer progression. Tumor however, the prognosis is very good, with a ten year Survival associated antigens including peptides, proteins and poly rate of greater than 85%. Current treatment modalities saccarides have been utilized in microarray or ELISA include radiation therapy, Surgery, and androgen deprivation experiments to profile cancer and normal Sera. therapy. Treatment of prostate cancer can have serious side 0010 Prostate cancer progression involves multiple steps effects, including impairment of sexual or urinary function, including: prostatic intraepithelial neoplasia (PIN), localized thus the decision to intervene should be made on the most carcinoma, invasive carcinoma and metastasis. The genetic reliable criteria possible. and epigenetic events in prostate tumorigenesis include the 0005 Accurate, early diagnosis of prostate cancer has loss of function of tumor Suppressors, cell cycle and apop proven challenging however, as the current diagnostic test tosis regulators, proteins in metabolism machinery and for prostate cancer relies on detection of prostate-specific stress response, angiogenesis and metastasis related mol antigen (PSA) levels, an indicator that also correlates with ecules (Abate-Shen et al. (2000) "Molecular genetics of benign prostate hypertrophy (BPH), a non-life threatening prostate cancer.’ Genes Dev. 14(19):2410-34; Ciocca et al. condition that does not increase cancer risk. BPH is found in (2005) “Heat shock proteins in cancer: diagnostic, prognos about half of men at age 60, and about 90% of men reaching tic, predictive, and treatment implications. Cell Stress the age of 85. The PSA test is currently widely used in Chaperones 10(2):86-103). These proteins could potentially prostate cancer diagnosis. In general, a blood serum level of serve as PCa antigens and induce autoantibody response in 4 ng per ml or higher of PSA is considered suggestive of PCa patients. Furthermore these induced autoantibodies can prostate cancer, while a PSA level of 10 ng per ml or higher be used for PCa diagnosis either in a single- or multiple is considered highly suggestive of prostate cancer. While the marker format. While PCa results from the deregulated PSA test has a fairly good sensitivity (80%), it suffers from proliferation of epithelial cells, BPH majorly results from a false positive rate that approaches 75%. It is estimated that normal epithelial cell proliferation which does not fre for PSA values of 4-10 ng/mL, only one true diagnosis of quently lead to malignancy (Ziada et al. (1999) “Benign prostate cancer was found in approximately 4 biopsies prostatic hyperplasia: an overview, Urology 53(3 Suppl performed (Catalona et al. (1994) “Comparison of digital 3D): 1-6). Immune profiling using serum samples from PCa rectal examination and serum prostate specific antigen in the and BPH patients will help to identify biomarkers with early detection of prostate cancer: results of a multicenter unique autoantibody patterns in PCa, clearly distinguishable clinical trial of 6,630 men.” J Urol. 151(5):1283-90). Tests from the BPH autoantibody signature(s). that measure the ratio of free to total (free plus bound) PSA do not have significantly greater specificity or sensitivity SUMMARY OF THE INVENTION than the standard PSA test. 0011. The invention relates generally to the detection of 0006 Recently a urinary test has been developed based autoantibodies related to cancer, and more particularly to on detection of the PCA3 transcript. However, the reliability methods of diagnosing, prognosing, and monitoring prostate of the test depends on its being performed in conjunction cancer using panels of antigens for the detection of autoan with an attentive digital rectal exam (DRE), which means tibodies.
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