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Annexin a2 as immunological target

Inactive Publication Date: 2011-12-01
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0012]Still another aspect of the invention is a method of screening for candidate drugs which inhibit tumor invasion and/or metastasis. One or more test substances are contacted with pancreatic cancer cells in culture. Subcellular localization of ANXA2 after the contacting is determined. One or more test substances are identified as candidate drugs for inhibiting tumor invasion and/or metastasis if the one or more test substances inhibit translocation of ANXA2 to the cell surface.
[0013]According to another aspect of the invention a method of screening for candidate drugs which inhibit tumor invasion and/or metastasis is provided. One or more test substances is contacted with pancreatic cancer cells in culture. Phosphorylation status of Tyr23 of ANXA2 is determined. One or more test substances are identified as candidate drugs for inhibiting tumor invasion and/or metastasis if the one or more test substances inhibit phosphorylation of Tyr23 of ANXA2.
[0014]Yet

Problems solved by technology

Lack of early diagnosis and effective systemic treatment are major reasons that account for these dismal survival rates.
However, drugs that target these molecular abnormalities have not yet translated into improved clinical responses (Strimpakos, Saif et al.
However, little is known about the molecular mechanisms underlying the early invasion and metastasis of PDAC.
However, the clinical significance of these TAAs and their antibodies largely remains unclear.

Method used

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  • Annexin a2 as immunological target
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  • Annexin a2 as immunological target

Examples

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example 1

Antibody Response Signature in Vaccinated Patients

[0097]Here we report on antibody response in serum samples collected before and after vaccination which is specific for proteins extracted from the tumor vaccine lines. We found that not only did most of the patients who survived longer than 3 years develop an antibody response in their post-vaccination sera, but they showed the highest number of antibodies specific for a variety of proteins of different sizes. Using a proteomics approach, we identified a panel of proteins for which specific antibody titers were elevated in the post-vaccination serum samples, which translated to a favorable clinical outcome.

[0098]Study design and clinical evaluation of a phase II trial on an allogeneic GM-CSF secreting pancreatic tumor vaccine were published elsewhere (28). Briefly, 60 patients with stage 1, 2, and 3 resected PDA were enrolled. First vaccination was administered 8 weeks after pancreaticoduodenectomy and followed 1 month later by a 6-...

example 2

Antibody Response Correlates with Favorable Clinical Response

[0099]The above Western blot result also showed that the highest number of antibody-reactive protein bands, though not necessary the highest antibody titer, was observed when probed with sera collected after 3rd vaccination (FIG. 1). To expand the analysis to all 60 patients, serum samples collected at pre-vaccination (60 patients) and post-3rd vaccination (33 out of 60 patients) were tested for vaccine-specific antibody response using Western blot analysis. Serum samples from 22 healthy donors were also included as controls. Sixty vaccinated patients were divided into 3 groups based on survival. Group A (n=12) are patients who completed all vaccine schedule and survived greater than 3 years at the end of this trial. Majority of patients in this group developed antibody response in their post-vaccination sera as demonstrated by either appearance of new antibody activities or an elevated titer of existing antibody activitie...

example 3

Identification of Antibody-Reactive Proteins by Proteomics

[0100]We used a serological proteomics approach to identify the antigens that could be recognized by antibodies detected in serum samples from clinical responders. To reduce sample complexity and to enrich low abundant proteins, we pre-fractionated total cell lysate on a ZOOM IEF Fractionator (Invitrogen) into 2 fractions which contained proteins with isoelectric points (pI) from pH 3-6 and from pH 7-10, respectively. Each fraction was further subject to 2-dimensional electrophoresis (2-DE) and immunoblotting analysis with pre-versus post (3rd vaccine)-vaccination serum samples from the 4 long-term survivors (patients 9, 12, 27 and 53). Corresponding antibody-reactive protein spots on Coomassie bright blue (CBB)-stained gels were excised and digested with trypsin. Resulting peptides were analyzed by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. A representative result from patient #...

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Abstract

AnnexinA2 (ANXA2), a member of the Annexin family of calcium-dependent, phospholipid binding proteins, is one of a panel of identified antigens recognized by the post-vaccination sera of patients who demonstrated prolonged disease-free survival following multiple vaccinations. AnnexinA2 is abundantly expressed in pancreatic adenocarcinomas and cell surface / membrane AnnexinA2 increases with the progression from premalignant lesions to invasive pancreatic adenocarcinomas. The cytoplasmic to cell surface translocation of AnnexinA2 expression is critical for pancreatic cancer cell invasion. In addition, phosphorylation of AnnexinA2 at Tyrosine 23 is important for its localization to the cell surface and for the invasion of pancreatic cancer cells. Finally, loss of AnnexinA2 leads to the loss of the Epithelial-Mesenchymal Transition.

Description

[0001]This invention was made in part using funds from the National Institutes of Health, Grant No. P50CA062924. The U.S. Government retains certain rights in the invention according to the terms of the grant.TECHNICAL FIELD OF THE INVENTION[0002]This invention is related to the area of tumor immunology. In particular, it relates to highly immunogenic proteins found on tumor cells.BACKGROUND OF THE INVENTION[0003]Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignant disease with a median survival of less than 6 months and an overall 5-year survival rate of 1-4% (Pierantoni, Pagliacci et al. 2008). Lack of early diagnosis and effective systemic treatment are major reasons that account for these dismal survival rates. Morphologic and genetic analyses have implicated pancreatic intraepithelial neoplasm (PanIN) as a precursor lesion of human PDAC. PanINs appear to evolve in a stepwise manner through stages (PanIN1A, 1B, 2, 3) that display increasing cellular atypia and accu...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P35/00A61K39/00C07H21/02G01N33/566
CPCA61K38/00A61K2039/505C07K16/18G01N2500/10G01N33/5011G01N2500/04C07K16/303A61K39/0005A61K38/193A61K39/0011A61P35/00C12N5/0693A61K39/39558A61K2039/575C07K2317/73G01N33/6893G01N2333/4724G01N2800/52
Inventor JAFFEE, ELIZABETH MARIONHUANG, LANQINGZHENG, LEI
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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