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New anti-human ig[beta] antibody

A human and antibody technology, applied in the direction of antibodies, anti-animal/human immunoglobulins, fungi, etc., can solve the problem that humoral immunity cannot be properly controlled

Active Publication Date: 2017-04-19
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] For association with rheumatoid arthritis, it has been reported that humoral immunity cannot be properly controlled in FcγRIIb knockout mice (Nature, Vol.379, p.346-349, 1996; J. Immunol., Vol. .163, p.618-622, 1999), and increased susceptibility to collagen-induced arthritis (J.Exp.Med., Vol.189, p.187-194, 1999)

Method used

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  • New anti-human ig[beta] antibody
  • New anti-human ig[beta] antibody
  • New anti-human ig[beta] antibody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0184] (Example 1: acquisition of human and monkey Igβ-Flag proteins)

[0185] A protein in which a Flag tag is bound to human Igβ (human Igβ-Flag protein) and a protein in which a Flag tag is bound to monkey Igβ (monkey Igβ-Flag protein) were obtained. Human Igβ-Flag gene (SEQ ID NO: 13) was introduced into GS vector pEE6.4 (Lonza Biologics, Inc.). The monkey Igβ-Flag gene (SEQ ID NO: 14) was introduced into GS vector pEE6.4 (Lonza Biologics, Inc.). The correspondingly prepared vector genes were transferred to FreeStyle 293 cells (Life Technologies, Inc.) using FreeStyle MAX reagent (life Technologies, Inc.). The corresponding cells were cultured in a serum-free culture system for 1 week using FreeStyle 293 expression medium (Life Technologies, Inc.), and culture supernatants containing human Igβ-Flag protein and monkey Igβ-Flag protein were obtained, respectively. The protein was purified from the obtained culture supernatant using an anti-Flag M2 antibody affinity gel (SI...

Embodiment 2

[0186] (Example 2: Acquisition of anti-human Igβ antibody)

[0187] In order to obtain an anti-human Igβ antibody, the human Igβ-Flag protein and monkey Igβ-Flag protein obtained in Example 1 were injected into C3H / HeJJmsSlc-lpr / lpr mice (Japan SLC, Inc.) together with an adjuvant, using To elicit an immune response for immunization. The mice were immunized several times and a final immunization was performed. The spleen and lymph nodes of the immunized mice were extracted according to conventional methods, and lymphocytes were collected and subjected to cell fusion with mouse myeloma cells SP2 / 0 (ATCC CRL-1581), thereby preparing hybridomas. Limiting dilution samples of the hybridomas were prepared, and the hybridomas were monocloned. The corresponding clones were expanded and cultured, the medium was replaced with a serum-free medium called Hybridoma SFM (Life Technologies, Inc.), and then the clones were cultured for 3 to 5 days. The antibody was purified from the obtain...

Embodiment 3

[0189] (Example 3: Preparation of humanized antibody)

[0190] The CDRs of the heavy and light chains of CL6_40 were grafted to other human antibodies, and the genes of the heavy and light chains of multiple humanized antibodies were prepared. Expression vectors containing both heavy and light chain genes of the corresponding humanized antibodies were constructed using GS vectors (Lonza Biologics, Inc.). Specifically, the gene encoding the signal sequence (N.Whittle et al., ProteinEng., Vol.1, p.499-505, 1987) and the constant region gene of human Igγ1 with amino acid mutations S239D, H268D and L328W (identified by SEQ ID NO: 1 base sequence from 358 to 1350 bases) were respectively connected to the 5' side and 3' side of the heavy chain variable region gene of the corresponding humanized antibody, and then the heavy chain gene was inserted into GS vector pEE6.4. In addition, the gene encoding the signal sequence (N. Whittle et al., as described above) and the constant regio...

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Abstract

The invention provides an anti-human Ig[beta] antibody in which BCR and Fc[gamma]RIIb are crosslinked and which has a more enhanced immunosuppressive function compared to conventional antibodies. An anti-human Ig[beta] antibody including: a heavy-chain variable region that includes a CDR 1 comprising an amino acid sequence from amino acid numbers 31-35 of SEQ ID NO: 2, a CDR 2 comprising an amino acid sequence from amino acid numbers 50-65 of SEQ ID NO: 2, and a CDR 3 comprising an amino acid sequence from amino acid numbers 98-108 of SEQ ID NO: 2; a light-chain variable region that includes a CDR 1 comprising an amino acid sequence from amino acid numbers 24-38 of SEQ ID NO: 4, a CDR 2 comprising an amino acid sequence from amino acid numbers 54-60 of SEQ ID NO: 4, and a CDR 3 comprising an animo acid sequence from amino acid numbers 93-101 of SEQ ID NO: 4; and a heavy-chain constant region, said region being a human Ig[gamma]1 constant region having S239D, H268D, and L328W amino acid variations.

Description

technical field [0001] The present invention relates to novel anti-human Igβ antibodies useful as active ingredients of pharmaceutical compositions. Background technique [0002] The B cell receptor (BCR) is composed of membrane immunoglobulin (mIg) molecules assembled with heterodimers of Igα (CD79A) and Igβ (CD79B). Antigen binds to mIg and allows the receptor to aggregate, and the Igα / Igβ subunits transmit the signal to the interior of the B cell (Mol. Immunol., Vol.41, p.599-613, 2004). [0003] For the Fcγ receptor (FcγR) protein family, which are Fc receptors for IgG antibodies, FcγRIa (CD64A), FcγRIIa (CD32A), and FcγRIIIa (CD16A) with immunoreactive functions and FcγRIIb with immunosuppressive functions have been reported (CD32B). It has been reported that when BCR and FcγRIIb on B cells are cross-linked by IgG immune complexes, the activity of B cells is inhibited, and thus the proliferation and antibody production of B cells are inhibited (Nat. Rev. Immunol., Vol...

Claims

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Application Information

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IPC IPC(8): C12N15/09A61K39/395A61P37/06C07K16/28C07K16/46C12N1/15C12N1/19C12N1/21C12N5/10C12N15/02C12P21/08
CPCA61K2039/505C07K16/2803C07K2317/24C07K2317/33C07K2317/76C07K2317/565C07K2317/52C07K2317/72C07K2317/40A61P37/06C12N15/09C12N15/02C07K16/28C07K16/46C12N5/10A61K39/395C12N15/63C07K2317/56C07K2317/92
Inventor 山宿大介关睦美本田贵史久保聪司曾我真司森中绍文
Owner ASTELLAS PHARMA INC
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