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Glypican-3 peptide reagents and methods

A phosphatidylinositol and proteoglycan technology, applied in the field of glypican-3 peptide reagents and methods, can solve the problems of shortened survival time and low effect

Pending Publication Date: 2020-02-21
RGT UNIV OF MICHIGAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in a clinical study (SHARP), sorafenib showed only a minimal (~3 months) survival advantage over placebo [Llovet et al, NEngl J Med, 359:378 -390(2008)], and sorafenib may be less effective in Asian patients compared with Caucasian patients, in which a significantly shorter survival time was found (6.5 months vs. 7.9 months) [Cheng et al., "Lancet Oncol", 10:25-34 (2009)]

Method used

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  • Glypican-3 peptide reagents and methods
  • Glypican-3 peptide reagents and methods
  • Glypican-3 peptide reagents and methods

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example 1

[0097] GPC3 expression

[0098] We use datasets GSE14520 [Roessler et al., Cancer Res., 70:10202-10212 (2010)] and GSE44074 [Ueda et al., Genomics, 101:238-248 (2013 )] identified GPC3 as a promising target for detection and treatment of HCC. Expression levels of GPC3 showed large differences in P-values ​​and mean fold changes compared to non-tumors, Picture 1-1 a. difference by log 2 Displays the distribution of gene expression levels to reflect, as Picture 1-1The dataset GSE14520 in B is shown. Figure 1-2 B display with Picture 1-1 The same dataset GSE14520 is shown in B, and an additional dataset GSE44074 is shown (ie both datasets are shown). The ROC curve for this data showed a sensitivity of 89% and a specificity of 92%, with an area under the curve (AUC) of 0.92, Picture 1-1 c. These results suggest that GPC3 is a promising target for HCC. Figure 1-2 A is shown under additional analysis with Picture 1-1 The same data as shown in A. Figure 1-2 C is si...

example 2

[0101] Peptides specific for GPC3

[0102] A panel of candidate peptides specific for GPC3 was identified using phage display technology. Peptide selection was performed using an M13 phage library expressing about 10 of each individual sequence. 9 unique clones [Zhou et al., Clin Transl Gastroenterol, 6:e101 (2015); Joshi et al., Bioconjug Chem, 27:481-494 (2016); Rabinsky et al., Cell Mol Gastroenterol Hepatol, 2:222-237 (2016)]. Biopanning of the library was performed against purified recombinant GPC3 core protein immobilized in 6-well plates. Four rounds of biopanning were performed using decreasing amounts (100, 80, 60 and 40 μg) of GPC3 core protein in successive rounds to increase binding specificity. Bound phage were eluted, amplified, precipitated, and titrated using standard protocols, and enriched clones from the candidate pool were sequenced to identify lead candidate sequences: ALLANHEELF (SEQ ID NO:2), GLHTSATNLYLH (SEQ ID NO:3 ), SGVYKVAYDWQH (SEQ ID NO: 4) a...

example 3

[0107] siRNA knockdown of GPC3

[0108] The specificity of lead candidate peptide reagent binding was verified by siRNA knockdown of GPC3 in human HCC cells. Cells were transfected with siRNA to knockdown the cell surface expression of GPC3. In confocal microscopy, Figure 6-1 A shows ALL*-Cy5.5 peptide reagent, and Figure 6-1 B shows strong binding of AF488-labeled anti-GPC3 antibody to the cell surface of Hep3B cells (arrows). These cells were transfected with non-targeting siRNA (siCL) to serve as controls. Figure 6-1 C, F show minimal binding of the scrambled (control) peptide QLE*-Cy5.5 to the same cells. Figure 6-1 D and E show that for Hep3B cells transfected with siRNA (siGPC3) to knock down the expression of GPC3, the fluorescence intensity of peptide reagent and anti-GPC3 antibody decreased about 4 times, respectively. Figure 6-1 G shows measurements of fluorescence intensity for images collected in triplicate. Figure 6-1 H shows western blot of GPC3 expre...

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Abstract

The present invention is directed to glypican-3-specific peptide reagents, methods for detecting hepatocellular carcinoma cells using the peptide reagents, and methods for targeting hepatocellular carcinoma cells using the peptide reagents.

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 468,626, filed March 8, 2017, the entire contents of which are incorporated herein by reference. [0002] Incorporation by Reference of Electronically Submitted Materials [0003] Incorporated by reference in its entirety is the computer readable nucleotide / amino acid sequence listing filed concurrently with this document and identified as follows: 1,717 byte ASCII (text) titled "50687_SeqListing.txt" created on March 6, 2018 document. technical field [0004] The present invention relates to Glypican-3 specific peptide reagents, methods of detecting hepatocellular carcinoma cells using the peptide reagents, and methods of targeting hepatocellular carcinoma cells using the peptide reagents. Background technique [0005] Hepatocellular carcinoma (HCC) is the cause of approximately 800,000 deaths worldwide and represents the second most common cause of cancer death worldwide. HCC is a prim...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/66A61B5/055A61K38/04A61K38/10A61K47/44A61K47/64A61P35/00
CPCA61K49/0032A61K49/0056A61K47/62A61K47/6907C07K7/08C07K1/13C07K7/06G01N33/68G01N33/57438G01N2800/52A61P35/00A61K47/55A61K49/0043G01N33/582
Inventor J·周T·D·王Z·李B·P·乔希
Owner RGT UNIV OF MICHIGAN
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