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anti-muc1 antibody

An antibody and antigen technology, applied in the direction of antibodies, anti-tumor drugs, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve the problems of insufficient selectivity and unclear sugar chain specificity, etc. achieve less side effects

Inactive Publication Date: 2011-11-30
SHIONOGI & CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

7F11 and 1E4 bind to MUC1 with added sugar chains, but the specificity of sugar chains has not been clarified
[0010] In the Panko monoclonal antibody disclosed in Patent Document 4, the selectivity is not sufficient, and therefore, there is still a need for novel therapeutic combinations capable of selectively binding to tumor-associated MUC1 and reducing, reversing or preventing its effects in cancer thing

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0267] (Example 1: Synthesis of MUC1Tn20-mer glycopeptide)

[0268] Synthesis of Example Compound 1

[0269] H-His-Gly-Val-Thr-Ser-Ala-Pro-Asp- Thr (Galβ1→3GalNAcα)-Arg-Pro-Ala-Pro-Gly-Ser-Thr-Ala-Pro-Pro-Ala-NH 2 (1)

[0270]When synthesizing the glycopeptide solid phase, use Rink Amide-PEGA resin (0.05mmol / g, 500mg, 25μmol) as the solid phase carrier. For the amino acid elongation reaction, under the condition of microwave irradiation (40W, 2450MHz, 50℃), in the DMF solution of Fmoc-amino acid derivative (75μmol), HBTU (75μmol), HOBt (75μmol), DIEA (150μmol) React for 5 minutes. For sugar chain substitution amino acid elongation reaction, use 1.5 equivalents of Fmoc-Thr(Ac6 core1)-OH: N-α-Fmoc-O-[O-(2,3,4,6-tetra-O-acetyl -β-D-galactopyranosyl)-(1→3)]-4,6-di-O-acetyl-2-acetamide-2-deoxy-α-D-galactopyranosyl}- L-threonine was reacted under the same conditions for 20 minutes. Acetylation of unreacted amino groups was carried out in 13 Mm HOBt in acetic anhydride / DIEA...

Embodiment 2

[0365] (Example 2: Production of MUCl-specific antibody)

[0366] (preparation of immunogen)

[0367] Dissolve 5 mg of 2,3-ST(DT*R)-20 (Compound No. 2 in Table 1) in 0.2 ml of distilled water, add 0.2 ml of an aqueous solution containing 860 μg of Sulfo-SMCC (manufactured by PIERCE) and 0.2 ml of 0.1 M phosphate buffer (pH 7.4), and allowed to react at room temperature for 1 hour. 200 µg of Sulfo-SMCC was added twice to the reaction solution, and the maleimidated compound 2 was purified by HPLC, followed by freeze-drying.

[0368] Dissolve 18.2 mg of BSA (manufactured by SIGMA-ALDRICH) in 0.2 ml of 0.2 M phosphate buffer (pH 7.4), add 0.2 ml of an aqueous solution containing 6 mg of Sulfo-LC-SPDP (manufactured by PIERCE), and react at room temperature 2 hours, and then react overnight at 4°C. BSA-SH in the reaction liquid was subjected to gel filtration and purification using a PD-10 column (manufactured by GE Healthcare). Gel filtration was performed on a PD-10 column equ...

Embodiment 3

[0374] (Example 3: Determination of specificity of antibody)

[0375] (sugar chain specific)

[0376] 15 µl of MUCl antibody-containing buffer A was added to the anti-mouse IgG antibody immobilized plate, and allowed to react at room temperature for 3 hours. Next, wash each well 3 times with 90 μl washing solution, and then add streptavidin-HRP and biotin-Tn(DT*R)-100 (compound No. 21 in Table 1), and T(DT*R) respectively. R)-20 (Compound No. 1), 2,3-ST(DT*R)-20 (Compound No. 2), Tn(DT*R)-20 (Compound No. 3), STn(DT*R)-20 (Compound No. 4), 2,3ST6G(DT*R)-20 (Compound No. 6), 2,3ST6L(DT*R)-20 (Compound No. 7), 2,3-ST6SL(DT*R)-20 (Compound No. 8), C6(DT*R)-20 (Compound No. 9), ST2-6(DT*R)-20 (Compound No. 10), dST(DT*R)-20 (Compound No. 11), 2. 15 μl of buffer A of 3ST(VT*S)-20 (Compound No. 12) and 40 (Compound No. 13) were reacted at 4°C for 16 hours. Next, each well was washed 3 times with 90 μl of washing solution, then 15 μl of TMB+-Substrate-Chromogen (manufactured by D...

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Abstract

The object of the present invention is to provide antibodies specific to cancer cells that do not bind to normal cells. The inventors of the present invention found that: using 2,3ST glycopeptides as antigens to immunize animals, the antibodies obtained unexpectedly, significantly and specifically recognize cancer-specific sugar chains, and then can recognize and kill cancer cells expressing such Cancer cells with specific sugar chains of MUC1, thereby solving the above-mentioned problems. The present invention provides an antibody, an antigen-binding fragment thereof, or a MUCl-binding molecule, which is, for example, 100-fold or more specific for a cancer-associated structure of MUCl as compared to a normal tissue-associated structure of MUCl.

Description

technical field [0001] The present invention relates to the technology in the field of antibodies. If further specified, it relates to an anti-Mucin-1 antibody and a cancer treatment technology using the antibody. Background technique [0002] Mucin-1 (Mucin1, hereinafter also referred to as MUC1 in this specification), which is a kind of mucin, is a tumor-associated antigen and is a high-molecular-weight glycoprotein expressed in various adenocarcinomas. Studies have shown that: in this protein, the extracellular domain of the indispensable membrane glycoprotein is mainly composed of 20 amino acid core sequences rich in serine, threonine and proline (hereinafter also referred to as "Tn20-mer" in this specification). ; 30-90 tandem repeats of HGVTSAPDTRPAPGSTAPPA (SEQ ID NO: 1)). The repeat number of "Tn20-mer" expressed by individuals is genetically determined, resulting in size polymorphism. [0003] Minimal sequence recognition for nearly all MUCl-reactive mAbs resides...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/30A61K38/00A61K39/395A61K49/00A61P35/00A61P43/00C12N15/13
CPCC07K2317/34A61K38/00C07K2317/94A61K2039/505C07K16/3092C07K2317/732A61P35/00A61P43/00C07K16/00
Inventor 西村绅一郎比能洋沼田义人小野田顺二内藤正一大薮巨树
Owner SHIONOGI & CO LTD
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