Antibody-drug conjugate having improved stability and use thereof

Abstract

The present invention relates to an antibody-drug conjugate comprising a drug conjugated to an antibody, a preparation method thereof and the use thereof.

1 . An antibody-drug conjugate comprising an immunosuppressive agent conjugated to the N-terminal amino acid residue of the heavy chain or light chain of an antibody,
 wherein the immunosuppressive agent is site-specifically conjugated to the N-terminal α-amine group of native first amino acid of the heavy chain or light chain of the antibody, and   the immunosuppressive agent is conjugated to the antibody by a linker having a reactive aldehyde group, and the conjugate is produced through reductive alkylation by the aldehyde group.   
     
     
         2 . The antibody-drug conjugate of  claim 1 , wherein the antibody includes full-length antibodies or antibody fragments containing antigen binding domains. 
     
     
         3 . The antibody-drug conjugate of  claim 2 , wherein the antibody is selected from the group consisting of IgG, scFv, Fv, Fab, Fab′, and F(ab′) 2 . 
     
     
         4 . The antibody-drug conjugate of  claim 1 , wherein the immunosuppressive agent is a cytokine antagonist. 
     
     
         5 . The antibody-drug conjugate of  claim 4 , wherein the cytokine antagonist is an interleukin antagonist. 
     
     
         6 . The antibody-drug conjugate of  claim 1 , wherein the immunosuppressive agent is a cytokine inhibitor. 
     
     
         7 . The antibody-drug conjugate of  claim 4 , wherein the cytokine inhibitor is an interleukin inhibitor. 
     
     
         8 . The antibody-drug conjugate of  claim 1 , wherein the antibody is selected from the group consisting of Trastuzumab, Lorvotuzumab, Brentuximab, and Glembatumumab. 
     
     
         9 . A pharmaceutical composition for treating autoimmune disease, which comprises the antibody-drug conjugate of  claim 1 . 
     
     
         10 . A method for preparing the antibody-drug conjugate of  claim 1 , the method comprising conjugating the immunosuppressive agent to the N-terminal α-amine group of the heavy chain or light chain of the antibody, by reacting an antibody with an immunosuppressive agent containing a reactive group capable of crosslinking with an α-amine group. 
     
     
         11 . The method of  claim 10 , further comprising separating the antibody-drug conjugate from a reaction product including the antibody and the immunosuppressive agent. 
     
     
         12 . The method of  claim 10 , wherein the reactive group capable of crosslinking with the α-amine group is selected from the group consisting of isothiocyanate, isocyanate, acyl azide, NHS ester, sulfonyl chloride, aldehyde, glyoxal, epoxide, oxirane, carbonate, aryl halide, imidoester, carbodiimide, anhydride, and fluorophenyl ester. 
     
     
         13 . A method for treating autoimmune disease, comprising administering the antibody-drug conjugate of  claim 1  to a subject having autoimmune disease. 
     
     
         14 . The method of  claim 13 , wherein the autoimmune disease is rheumatoid arthritis, systemic scleroderma, systemic lupus erythematosus, atomic dermatitis, psoriasis, alopecia areata, asthma, Crohn's disease, Behcet's disease, Sjögren's syndrome, Guillain-Barre syndrome, chronic thyroiditis, multiple sclerosis, polymyositis, ankylsoing spondylitis, fibrositis, or polyarteritis nodosa. 
     
     
         15 . The method of  claim 13 , wherein the antibody of the antibody-drug conjugate includes full-length antibodies or antibody fragments containing antigen binding domains. 
     
     
         16 . The method of  claim 13 , wherein the antibody of the antibody-drug conjugate is selected from the group consisting of IgG, scFv, Fv, Fab, Fab′, and F(ab′) 2 . 
     
     
         17 . The method of  claim 13 , wherein the immunosuppressive agent of the antibody-drug conjugate is a cytokine antagonist. 
     
     
         18 . The method of  claim 17 , wherein the cytokine antagonist is an interleukin antagonist. 
     
     
         19 . The method of  claim 13 , wherein the immunosuppressive agent of the antibody-drug conjugate is a cytokine inhibitor. 
     
     
         20 . The method of  claim 19 , wherein the cytokine inhibitor is an interleukin inhibitor. 
     
     
         21 . The method of  claim 13 , wherein the antibody of the antibody-drug conjugate is selected from the group consisting of Trastuzumab, Lorvotuzumab, Brentuximab, and Glembatumumab.