Immunotherapy of autoimmune disorders

An autoimmune disease, selected from the technology, applied in the field of producing the conjugate, cytotoxic drug/B cell depleting agent conjugate, B cell depleting agent conjugate, combined therapy, can solve the inability of autoimmune disease Effectively treat issues such as autoimmune diseases

Inactive Publication Date: 2007-09-12
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Currently available treatments for autoimmune diseases, such as antibo

Method used

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  • Immunotherapy of autoimmune disorders
  • Immunotherapy of autoimmune disorders
  • Immunotherapy of autoimmune disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0317] B cell depletion and anti-CD22 / calicheamicin immunoconjugate inhibit collagen-induced arthritis in a C57BL / 6 mouse model.

[0318]The study was carried out to test the role of B cell depletion in a mouse model of rheumatoid arthritis. The B cell depleting compound used in this study was mouse anti-CD22 mAb (Cy34.12) conjugated to calicheamicin, a member of the enediyne class of antitumor antibiotics ("conjugate").

[0319] Mice on a C57BL / 6 background were used due to Cy34.12 reactivity. In the in vitro cytotoxicity assay, purified primary B cells from male C57BL / 6 mice were cultured with the conjugate, and their proliferation under LPS stimulation was studied 48 hours after the initiation of culture.

[0320] In the in vivo cytotoxicity studies, male C57BL / 6 mice were injected intraperitoneally (i.p.) twice (day 0 and day 5) with the conjugate at a dose of 160 pg / kg / injection of calicheamicin. B cell depletion was monitored by flow cytometry in serial samples of bone...

Embodiment 2

[0324] Depletion of B cells targeting CD22 suppresses clinical and histological arthritis in a collagen-induced arthritis (CIA) model

[0325] This study was carried out to test the role of B cell depletion in a collagen-induced arthritis (CIA) model. The B cell depleting compound used in this study (referred to herein as CD22 / cal) is a conjugate of an anti-mouse CD22 monoclonal antibody (mAb) and N-acetyl-γ-calicheamicin dimethyl acid, belonging to the A member of the enediyne class of antitumor antibiotics. Anti-mouse CD22 is a mouse IgGl mAb purified from a Cy34.1 hybridoma (American Type Culture Collection, Rockville, MD). The synthesis of antibody / calicheamicin conjugates was previously described (Hamann, P.R. et al., An anti-CD33 antibody / calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of linker. Bioconjug Chem 13, 40-6 (2002)). The average CD22 / cal loading was 17 to 30 μg calicheamicin / mg antibody protein (1.2-2.6 moles calicheamicin / mole antib...

Embodiment 3

[0358] Effects of CD22 / cal-induced B cell depletion on clinical scores and antibody responses in a collagen-induced (CIA) model

[0359] B cell depletion in the CIA model

[0360] Complete Freund's adjuvant (CFA) (DifcoLaboratory, Detroit, MI) (containing 5 mg / ml inactivated Mycobacterium tuberculosis (H37Ra) 33 ) with 100 μg bovine type II collagen (CII) (Chondrex, Redmond, WA) subdermally immunized once (day 0) to induce CIA. CII-immunized mice were intraperitoneally injected twice (day 5 and day 10) with CD22 / cal or control GG5 / cal (160 μg / kg / injection). The paws were evaluated for clinical arthritis, and each paw was scored on a 4-point scale: 0, normal paw; 1, minimal swelling or redness; 2, redness and swelling of the entire front paw; 3, whole paw Redness and swelling of extremities; 4. Joint deformation and / or joint ankylosis.

[0361] Anti-Type II Collagen Antibody ELISA

[0362] The level of anti-II collagen IgG2b antibody was detected by standard ELISA method, t...

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Abstract

Compositions and methods for treating autoimmune diseases are described. In particular, the use of B cell depleting agents and cytotoxic drug/B cell depleting agent conjugates with a drug loading significantly higher than in previously reported procedures and with decreased aggregation and low conjugate fraction (LCF) in treating autoimmune diseases is described. Combination therapies and compositions for treating autoimmune diseases, including the B cell depleting agents, conjugates and/or anti-cytokine agents, are also described.

Description

field of invention [0001] The present invention relates to the treatment of autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), immune cytopenias (such as congenital thrombocytopenic purpura and autoimmune hemolytic anemia), autoimmune Compounds, conjugates of compounds, compositions and combination therapy for vasculitis and / or related disorders. In particular, the invention relates to B cell depleting agents such as B cell surface antigens targeting antibodies having cell surface epitope specificity and conjugates of such B cell depleting agents conjugated to cytotoxic drugs. For example, the invention relates to cytotoxic drug / B cell depleting agent conjugates, wherein the B cell depleting agent is an antibody specific for an epitope on a B cell. The invention also relates to methods for the production of said conjugates and their therapeutic use. In particular, the invention relates to methods for treating autoimmune diseases compr...

Claims

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Application Information

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IPC IPC(8): A61K51/00A61K39/395A61K39/40C07K16/00A61K39/38
Inventor A·耶尔K·杜努希－约安诺普洛斯
Owner WYETH LLC
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