US2021386865A1PendingUtilityA1

Method for selectively manufacturing antibody-drug conjugate

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Assignee: DAIICHI SANKYO CO LTDPriority: Jun 29, 2015Filed: Aug 26, 2021Published: Dec 16, 2021
Est. expiryJun 29, 2035(~8.9 yrs left)· nominal 20-yr term from priority
Inventors:Shigeru NoguchiKen SakuraiDaisuke Okajima
C07K 16/32A61K 47/68037A61K 31/407C07K 16/2896C07K 16/00A61K 31/40C07K 16/28A61K 45/00A61K 39/395A61K 31/4745A61K 39/3955A61P 35/00A61K 2039/505A61K 47/6849A61K 47/6801A61K 47/6851A61K 47/6803A61K 47/65
61
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Claims

Abstract

A method for producing an antibody-drug conjugate composition, comprising: (i) a step of reacting an antibody with a reducing agent in a buffer to reduce interchain disulfides, and (ii) a step of reacting drug linker intermediates with the antibody having thiol groups obtained in the step (i), wherein the reaction temperature in the step (i) is −10° C. to 10° C., and the average number of bound drugs in the produced antibody-drug conjugate composition is 3.5 to 4.5, and the content of antibody-drug conjugates in which four drug linkers are bound to heavy-light interchain thiols, in the produced antibody-drug conjugate composition is 50% or more; and an antibody-drug conjugate composition, wherein the content of antibody-drug conjugates wherein the average number of bound drugs is 3.5 to 4.5, and the content of antibody-drug conjugates in which four drug linkers are bound to heavy-light interchain thiols, is 50% or more.

Claims

exact text as granted — not AI-modified
1 . A method for producing an antibody having thiol groups, comprising the step of reacting an antibody with a reducing agent in a buffer to reduce interchain disulfides, wherein
 the reaction temperature is −10° C. to 10° C., and   the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the average number of bound drugs is 3.5 to 4.5, and the content of antibody-drug conjugates in which four drug linkers are bound to heavy-light interchain thiols is 50% or more.   
     
     
         2 . The method according to  claim 1 , wherein the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the average number of bound drugs is 4.0 to 4.1. 
     
     
         3 . The method according to  claim 1 , wherein the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the content of antibody-drug conjugates in which four drug linkers are bound to heavy-light interchain thiols, is in the range of 50% to 90%. 
     
     
         4 . The method according to  claim 3 , wherein the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the content of antibody-drug conjugates in which four drug linkers are bound to heavy-light interchain thiols, is in the range of 50% to 80%. 
     
     
         5 . The method according to  claim 4 , wherein the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the content of antibody-drug conjugates in which four drug linkers are bound heavy-light interchain thiols, is in the range of 50% to 70%. 
     
     
         6 . The method according to  claim 5 , wherein the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the content of antibody-drug conjugates in which four drug linkers are bound to heavy-light interchain thiols, is in the range of 50% to 60%. 
     
     
         7 . The method according to  claim 1 , wherein the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the content of antibody-drug conjugates in which four drug linkers are bound to heavy-heavy interchain thiols, is in the range of 5% or less. 
     
     
         8 . The method according to  claim 7 , wherein the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the content of antibody-drug conjugates in which four drug linkers are bound to heavy-heavy interchain thiols, is in the range of 1% or less. 
     
     
         9 . The method according to  claim 1 , wherein the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the content of antibody-drug conjugates in which two drug linkers are bound to heavy-heavy interchain thiols and two drug linkers are bound to heavy-light interchain thiols, is 5% or less. 
     
     
         10 . The method according to  claim 9 , wherein the produced antibody having thiol groups is used to produce an antibody-drug conjugate composition, wherein the content of antibody-drug conjugates in which two drug linkers are bound to heavy-heavy interchain thiols and two drug linkers are bound to heavy-light interchain thiols, is 1% or less. 
     
     
         11 . The method according to  claim 1 , wherein the reaction temperature is −5° C. to 5° C. 
     
     
         12 . The method according to  claim 11 , wherein the reaction temperature is −3° C. to 3° C. 
     
     
         13 . The method according to  claim 12 , wherein the reaction temperature is 0° C. to 2° C. 
     
     
         14 . The method according to  claim 13 , wherein the reaction temperature is 0° C. to 1° C. 
     
     
         15 . The method according to  claim 1 , wherein the reducing agent is used in an amount of 2 to 3 molar equivalents per molecule of the antibody. 
     
     
         16 . The method according to  claim 1 , wherein the reducing agent is tris(2-carboxyethyl)phosphine or a salt thereof. 
     
     
         17 . The method according to  claim 16 , wherein the salt of tris(2-carboxyethyl)phosphine is tris(2-carboxyethyl)phosphine hydrochloride. 
     
     
         18 . The method according to  claim 1 , wherein the buffer is a histidine buffer. 
     
     
         19 . The method according to  claim 1 , wherein the buffer comprises a chelating agent. 
     
     
         20 . The method according to  claim 19 , wherein the chelating agent is ethylenediaminetetraacetic acid. 
     
     
         21 . The method according to  claim 1 , wherein the antibody is an anti-TROP2 antibody, an anti-CD98 antibody, an anti-B7-H3 antibody, or an anti-HER2 antibody. 
     
     
         22 . The method according to  claim 21 , wherein the antibody is an anti-TROP2 antibody. 
     
     
         23 . The method according to  claim 21 , wherein the antibody is an anti-CD98 antibody. 
     
     
         24 . The method according to  claim 21 , wherein the antibody is an anti-B7-H3 antibody. 
     
     
         25 . The method according to  claim 21 , wherein the antibody is an anti-HER2 antibody.

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