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US 9,890,377 B2Granted
Antigen-binding molecule capable of binding to 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.
Claims24
A method of removing an antigen from plasma, the method comprising:
- (a) identifying an individual in need of having an antigen removed from the individual's plasma;
- (b) providing an antibody that 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 2 to 10,000, when KD is determined using a surface plasmon resonance technique in which the antibody is immobilized, the antigen serves as analyte, and the following conditions are used:
- 10mM MES buffer, 0.05% polyoxyethylenesorbitan monolaurate, and 150mM NaCl at 37° C.;
- and
- (c) administering the antibody to the individual, 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.
2 more elements
A method of removing an antigen from plasma in a subject, the method comprising:
- (a) identifying a first antibody that binds to the antigen through the antigen-binding domain of the first antibody;
- (b) identifying a second antibody that:
- (1) binds to the antigen through the antigen-binding domain of the second antibody,
- (2) is identical in amino acid sequence to the first antibody except having at least one amino acid of a variable region of the first antibody substituted with histidine and/or at least one histidine inserted into a variable region of the first antibody,
- (3) has a KD(pH5.8)/KD(pH7.4) value that is higher than the first antibody's KD(pH5.8)/KD(pH7.4) value, and is between 2 and 10,000, wherein KD(pH5.8)/KD(pH7.4) is defined as the ratio of KD for the antigen at pH 5.8 and KD for the antigen at pH 7.4 when KD is determined using a surface plasmon resonance technique in which the antibody is immobilized, the antigen serves as analyte, and the following conditions are used:
- 10mM MES buffer, 0.05% polyoxyethylenesorbitan monolaurate, and 150mM NaCl at 37° C.,
- (4) binds to the antigen in plasma in vivo,
- (5) dissociates from the bound antigen under conditions present in an endosome in vivo, and
- (6) is a human IgG or a humanized IgG;
- (c) identifying a subject in need of having his or her plasma level of the antigen reduced;
- and
- (d) administering the second antibody to the subject so that the plasma level of the antigen in the subject is reduced.
9 more elements
A method of removing an antigen from plasma in a subject, the method comprising:
- (a) identifying a first antibody that:
- (1) binds to the antigen through the antigen-binding domain of the first antibody,
- (2) is identical in amino acid sequence to a second antibody that binds to the antigen through the antigen-binding domain of the second antibody, except that at least one variable region of the first antibody has at least one more histidine residue than does the corresponding variable region of the second antibody,
- (3) has a KD(pH5.8)/KD(pH7.4) value that is higher than the second antibody's KD(pH5.8)/KD(pH7.4) value, and is between 2 and 10,000, wherein KD(pH5.8)/KD(pH7.4) is defined as the ratio of KD for the antigen at pH 5.8 and KD for the antigen at pH 7.4 when KD is determined using a surface plasmon resonance technique in which the antibody is immobilized, the antigen serves as analyte, and the following conditions are used:
- 10mM MES buffer, 0.05% polyoxyethylenesorbitan monolaurate, and 150mM NaCl at 37° C.,
- (4) binds to the antigen in plasma in vivo,
- (5) dissociates from the bound antigen under conditions present in an endosome in vivo, and
- (6) is a human IgG or a humanized IgG;
- (b) identifying a subject in need of having his or her plasma level of the antigen reduced;
- and
- (c) administering the first antibody at least once to the subject so that the plasma level of the antigen in the subject is reduced.
8 more elements
Dependencies are inferred from the claim text.