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Method and composition for treating cancer, killing metastatic cancer cells and preventing cancer metastasis using antibody to advanced glycation end products (AGE)

A technology for cancer metastasis and cancer cells, applied in chemical instruments and methods, drug combinations, antibody medical components, etc., and can solve problems such as inability to inhibit S phase

Pending Publication Date: 2018-12-21
SIWA CORP (US)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Deficient Rb fails to suppress S phase and downregulates p16, resulting in overexpression of p16 in hyperproliferative cells

Method used

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  • Method and composition for treating cancer, killing metastatic cancer cells and preventing cancer metastasis using antibody to advanced glycation end products (AGE)
  • Method and composition for treating cancer, killing metastatic cancer cells and preventing cancer metastasis using antibody to advanced glycation end products (AGE)
  • Method and composition for treating cancer, killing metastatic cancer cells and preventing cancer metastasis using antibody to advanced glycation end products (AGE)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] Example 1: In vivo study of administration of anti-glycation end product antibodies. This example demonstrates that anti-AGE antibodies can target cells that have AGE-modified proteins on the cell surface. Although the cells considered in this study are senescent cells, they can be considered as a model of metastatic cancer cells.

[0142] To examine the effect of anti-glycation end product antibodies, the antibodies were administered intravenously to aged CD1(ICR) mice (Charles River Laboratories) twice daily, once a week for three weeks (day 1, day 8 days and 15 days), followed by a 10-week no-treatment period. The test antibody was a commercially available mouse anti-glycation end product antibody raised against carboxymethyllysine conjugated to keyhole limpet hemocyanin, the carboxymethyllysine MAb (clone 318003) available from Available from R&D Systems, Inc. (Minneapolis, MN; Cat. No. MAB3247). A control reference of saline was used in control animals.

[0143...

Embodiment 2

[0158] Example 2: Testing Antibody Affinity and Kinetics

[0159] Use Nα, Nα-bis(carboxymethyl)-L-lysine trifluoroacetate (Sigma-Aldrich, St.Louis, MO) as a model substrate for the AGE-modified protein of cells used in Example 1 The affinity and kinetics of the test antibodies were analyzed. Using the series S sensor chip CM5 (GE Healthcare, Pittsburgh, PA) at BIACORE TM Label-free interaction assays were performed on a T200 (GE Healthcare, Pittsburgh, PA) with Fc1 set as blank and Fc2 immobilized with a test antibody (molecular weight 150,000 Da). The running buffer was HBS-EP buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA and 0.05% P-20, pH 7.4) at a temperature of 25°C. The software is BIACORE TM T200 Evaluation Software, Version 2.0. Dual references (Fc2-1 and buffer injection only) were used in the analysis and the data were fitted to a Langmuir 1:1 binding model.

[0160] Table 4: Experimental setup for affinity and kinetic analysis

[0161]

[0162] A plot of re...

Embodiment 3

[0163] Example 3: Construction and Production of Mouse Anti-AGE IgG2b Antibody and Chimeric Anti-AGE IgG1 Antibody

[0164] Murine and chimeric human anti-AGE antibodies were prepared. The DNA sequence of the murine anti-AGE antibody IgG2b heavy chain is shown in SEQ ID NO:12. The DNA sequence of the chimeric human anti-AGE antibody IgGl heavy chain is shown in SEQ ID NO:13. The DNA sequence of the murine anti-AGE antibody kappa light chain is shown in SEQ ID NO:14. The DNA sequence of the chimeric human anti-AGE antibody kappa light chain is shown in SEQ ID NO:15. The gene sequence was synthesized and cloned into a high expression mammalian vector. The sequence was codon optimized. Sequence confirmation of completed constructs was performed prior to proceeding with transfection.

[0165] HEK293 cells were seeded in shake flasks one day before transfection and grown using serum-free chemically defined media. The DNA expression constructs were transiently transfected into...

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Abstract

A method of treating cancer, killing metastatic cancer cells, killing potentially- malignant neoplasm cells and / or preventing cancer metastasis comprises administering to a subject a composition comprising an anti-AGE antibody. A method of diagnosing metastatic cancer comprises detecting an immune complex comprising an anti-AGE antibody bound to a cell expressing an AGE modification.

Description

Background technique [0001] Senescent cells are partially functional or nonfunctional cells and are in a state of proliferative arrest. Senescence is a unique state of cells and is associated with biomarkers such as the p16 biomarker Ink4a ("p16") activation and expression of β-galactosidase. Senescence begins with cellular damage or stress (eg, overstimulation by growth factors). Damage or stress adversely affects mitochondrial DNA in cells, causing it to generate free radicals that react with sugars in cells to form methylglyoxal (MG). MG then reacts with proteins or lipids to produce advanced glycation end products (AGE). In the case of the protein component lysine, MG reacts to form carboxymethyllysine, which is an AGE. AGEs are also formed by non-enzymatic reactions of sugars in the blood with external cellular proteins. [0002] Damage or stress to mitochondrial DNA also elicits a DNA damage response that induces cells to produce cell cycle arresting proteins. Thes...

Claims

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Application Information

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IPC IPC(8): C07K16/44A61K39/395
CPCA61K39/395C07K16/44A61P35/04A61K2039/505G01N33/574C07K2317/24C07K2317/92A61K39/3955A61K39/39558
Inventor 刘易斯·S·格鲁伯
Owner SIWA CORP (US)
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