Antigen-binding molecule capable of binding two or more antigen molecules repeatedly
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsTomoyuki Igawa, Shinya Ishii, Atsuhiko Maeda, Takashi Nakai
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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.
Claims21
A method of removing an antigen from plasma, the method comprising:
- administering an antibody to an individual in need of having an antigen removed from the individual's plasma, wherein the antibody binds to the antigen through the antigen-binding domain of the antibody and has 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 40 to 1,000, wherein the antibody binds to the antigen in plasma in vivo and dissociates from the bound antigen under conditions present in an endosome in vivo, and wherein the antibody is a human IgG or a humanized IgG.
A method of removing an antigen from plasma, the method comprising:
- administering an antibody to an individual in need of having an antigen removed from the individual's plasma, wherein the antibody binds to the antigen through the antigen-binding domain of the antibody and has been determined to have 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 40 to 1,000, wherein the antibody binds to the antigen in plasma in vivo and dissociates from the bound antigen under conditions present in an endosome in vivo, and wherein the antibody is a humanized IgG.
A method of removing an antigen from plasma, the method comprising:
- administering an antibody to an individual in need of having an antigen removed from the individual's plasma, wherein the antibody binds to the antigen through the antigen-binding domain of the antibody comprising one or more histidine substitutions at one or more heavy chain or light chain variable region positions and has 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 10 to 1,000, wherein the antibody binds to the antigen in plasma in vivo and dissociates from the bound antigen under conditions present in an endosome in vivo, and wherein the antibody is a human IgG or a humanized IgG.
A method of removing an antigen from plasma, the method comprising administering an antibody to an individual in need of having an antigen removed from the individual's plasma,
- wherein the antibody binds to the antigen through the antigen-binding domain of the antibody comprising one or more histidine substitutions at one or more heavy chain or light chain variable region positions and has 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 10 to 1,000,
- wherein the antibody binds to the antigen in plasma in vivo and dissociates from the bound antigen under conditions present in an endosome in vivo,
- wherein the antibody is a human IgG or a humanized IgG, and
- wherein the antibody has been selected by a process comprising:
- (i) introducing one or more histidine substitutions at one or more heavy chain or light chain variable region positions of a parent antibody that binds to the antigen through the antigen-binding domain of the antibody;
- and
- (ii) determining the KD of the antibody comprising one or more histidine substitutions at a first pH that is in the range of pH 6.7 to pH 10.0 and at a second pH that is in the range of pH 4.0 to pH 6.5.
Dependencies are inferred from the claim text.