Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly

Abstract

The present inventors discovered that antibodies having weaker antigen-binding activity at the early endosomal pH in comparison with that at the pH of plasma are capable of binding to multiple antigen molecules with a single antibody molecule, have long half-lives in plasma, and have improved durations of time in which they can bind to antigen.

1 . An antigen-binding molecule having a KD(pH5.8)/KD(pH7.4) value, defined as the ratio of KD for the antigen at pH 5.8 and KD for the antigen at pH 7.4, of 2 or higher. 
     
     
         2 - 8 . (canceled) 
     
     
         9 . A method for improving the pharmacokinetics of an antigen-binding molecule, for increasing the number of times of antigen-binding for an antigen-binding molecule, for increasing the number of antigens that can be bound by an antigen-binding molecule, for dissociating within a cell an antigen from an extracellularly-bound antigen-binding molecule, for releasing an antigen-binding molecule, which has been bound to an antigen and internalized into a cell, in an antigen-free form to the outside of the cell, or for increasing the ability of an antigen-binding molecule to eliminate an antigen in plasma by impairing the antigen-binding activity of the antigen-binding molecule at pH 5.8 as compared to that at pH 7.4. 
     
     
         10 - 14 . (canceled) 
     
     
         15 . The method of  claim 9 , wherein the KD(pH5.8)/KD(pH7.4) value, defined as the ratio of KD for the antigen at pH 5.8 and KD for the antigen at pH 7.4, is 2 or higher. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . A method for improving the pharmacokinetics of an antigen-binding molecule, for increasing the number of times of antigen-binding for an antigen-binding molecule, for increasing the number of antigens that can be bound by an antigen-binding molecule, for dissociating within a cell an antigen from an extracellularly-bound antigen-binding molecule, for releasing an antigen-binding molecule, which has been bound to an antigen and internalized into a cell, in an antigen-free form to the outside of the cell, or for increasing the ability of an antigen-binding molecule to eliminate an antigen in plasma by substituting at least one amino acid of the antigen-binding molecule with histidine, or inserting at least one histidine into the antigen-binding molecule. 
     
     
         19 - 23 . (canceled) 
     
     
         24 . The method of  claim 18 , wherein the histidine substitution or insertion increases the KD(pH5.8)/KD(pH7.4) value, defined as the ratio of the antigen-binding activity at pH 5.8 and the antigen-binding activity at pH 7.4, as compared to the KD(pH5.8)/KD(pH7.4) value before the histidine substitution or insertion. 
     
     
         25 . The method of  claim 9 , wherein the antigen-binding molecule has an antagonistic activity. 
     
     
         26 . The method of  claim 9 , wherein the antigen-binding molecule binds to a membrane antigen or a soluble antigen. 
     
     
         27 . The method of  claim 9 , wherein the antigen-binding molecule is an antibody. 
     
     
         28 - 50 . (canceled)