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Anti-glypican-3 antibody

A phosphatidylinositol and proteoglycan technology, applied in the direction of antibodies, anti-animal/human immunoglobulins, immunoglobulins, etc., can solve problems such as functions that have not been well elucidated

Inactive Publication Date: 2008-10-15
CHUGAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Glypican-3 (glypican-3, GPC3) is a family of heparan sulfate proteoglycans present on the cell surface, and it is suggested that GPC3 may be involved in cell differentiation in cancer cell development and growth, but its Functionality is still not well clarified

Method used

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  • Anti-glypican-3 antibody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Example 1: Generation of Fc-modified anti-GPC3 antibodies:

Embodiment 1-1

[0113] Example 1-1: Preparation of Fc box for mutagenesis:

[0114] The Fc-modified humanized anti-GPC3 antibody has the amino acid substitutions shown in the table below in the H-chain amino acid sequence shown in SEQ ID NO:19. Figure 1 shows the structure and preparation strategy of the Fc-modified antibody of the present invention.

[0115] V22

I332E

V209

S239D / A330L / I332E

V212

S239D / S298A / I332E

V922

S239D / K326T / I332E

V1608

S239D / S298A / K326T / I332E

V209nG1m(1)

S239D / A330L / I332E / D356E / L358M

[0116] Using the primers shown in SEQ ID NO: 1 to NO: 9, Fc-mutation cassettes for the construction of five Fc-modified antibodies named V22, V209, V212, V922 and V1608 were generated according to the PCR walking method. Specifically, universal primers F1 and universal R1 are used for V22, V209 and V922; primers 212-F1 and 212-F1 are used for V212 and V1608. Perform the first-stage PCR in the following...

Embodiment 1-2

[0143] Example 1-2: Preparation of vectors expressing Fc-modified anti-GPC3 antibodies

[0144] According to the gene (H-chain, SEQ ID NO: 10; L-chain, SEQ ID NO: 11) encoding the humanized anti-glypican-3 antibody previously prepared by the inventors, a A vector for expressing the Fc-modified anti-GPC3 antibody of the present invention, which is referred to as "wild type" in the following examples.

[0145] The amino acid sequences of the H-chain variable region and the L-chain variable region of the wild-type humanized anti-GPC3 antibody are shown in SEQ ID NO: 21 (ver.k) and SEQ ID NO: 22 (ver.a), respectively middle. The CDR sequences of the wild-type humanized anti-GPC3 antibody are shown below.

[0146] H-chain

[0147] CDR1 DYEMH (SEQ ID NO: 23)

[0148] CDR2 ALDPKTGDTAYSQKFKG (SEQ ID NO: 24)

[0149] CDR3 FYSYTY (SEQ ID NO: 25)

[0150] L-chain

[0151] CDR1 RSSQSLVHSNGNTYLH (SEQ ID NO: 26)

[0152] CDR2 KVSNRFS (SEQ ID NO: 27)

[0153] CDR3 SQNTHVPPT (SEQ ID ...

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Abstract

An anti-glypican-3 antibody comprising one or more amino acid substitutions introduced in the Fc region is disclosed. Preferably, in the anti-glypican-3 antibody, one or more of the amino acid residues at the positions 239, 298, 326, 330 and 332 in the Fc region are substituted with other amino acid residues. Since the Fc-modified anti-glypican-3 antibody of the invention exhibit enhanced ADCC activity, it is useful in treating cancers, such as hepatic cancer. Also disclosed are an anticancer agent comprising the anti-glypican-3 antibody of the invention and a pharmaceutically acceptable carrier, as well as a method of treating a patient with cancer comprising administering to the patient the anticancer agent of the invention.

Description

technical field [0001] The present invention relates to an anti-glypican-3 antibody. In particular, the present invention relates to an anti-glypican-3 antibody having a modification in the amino acid sequence of the Fc region and exhibiting enhanced ADCC activity. Background technique [0002] Glypican-3 (glypican-3, GPC3) is a family of heparan sulfate proteoglycans present on the cell surface, and it is suggested that GPC3 may be involved in cell differentiation in cancer cell development and growth, but its Functionality is still not well clarified. [0003] Certain GPC3-binding antibodies have been found to have cytostatic effects through their ADCC (antibody-dependent cytotoxicity) activity and CDC (complement-dependent cytotoxicity) (WO2003 / 000883, incorporated herein by reference in its entirety). [0004] In developing an anticancer agent utilizing the cytotoxic activity of an antibody, it is desirable to utilize an antibody having enhanced ADCC activity. Therefo...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/18A61P35/00
CPCC07K2316/52C07K2317/52C07K2317/732C07K16/303A61K2039/505C07K2317/24A61P35/00C07K2317/72C07K16/18A61K39/395C07K2317/524C07K2317/526
Inventor G·A·拉扎尔B·I·达希雅特冈部尚文杉本正道饭岛成幸周乡泉
Owner CHUGAI PHARMA CO LTD
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