Antibody buffering of a ligand in vivo

An antibody buffering method for maintaining a desired concentration range of a soluble small molecule or polypeptide ligand in a body compartment in a subject, comprising:

• (a) isolating one or a plurality of antibodies, or an antigen-binding fragment thereof, that has been generated in vivo or in vitro and that specifically binds to a small molecule or polypeptide ligand in solution;
• (b) determining, for each of the antibodies or antigen-binding fragments thereof of (a), an antibody dissociation constant, KD, for binding to the ligand:,
• (c) selecting, from among the antibodies or antigen-binding fragments thereof of (a), an antibody or an antigen-binding fragment thereof that has said antibody dissociation constant, KD, having a value as determined in (b) that is within tenfold of the desired concentration range of the ligand;
• and
• (d) administering to the subject simultaneously or sequentially and in either order at least one dose of said ligand and said antibody, or antigen-binding fragment thereof, selected in step (c), to attain the desired concentration range of the ligand as unbound free ligand in the subject,
• wherein the antibody-to-ligand molar ratio is approximately 1:1 or at least 2:1;
• whereby antibody buffering delays clearance of the ligand as a result of equilibrium distribution between (i) the ligand complexed to the antibody or antigen-binding fragment thereof and (ii) the unbound free ligand, such that the half-life of the ligand when administered with the antibody or antigen-binding fragment thereof is increased by at least two-fold relative to the half-life of the ligand when administered alone.

An antibody buffering method for maintaining a desired concentration range of a soluble small molecule or polypeptide ligand in a central nervous system compartment in a subject, comprising:

• (a) isolating one or a plurality of antibodies, or an antigen-binding fragment thereof, that has been generated in vivo or in vitro and that specifically binds to a small molecule or polypeptide ligand in solution;
• (b) determining, for each of the antibodies or antigen-binding fragments thereof of (a), an antibody dissociation constant, KD, for binding to the ligand;
• (c) selecting, from among the antibodies or antigen-binding fragments thereof of (a), an antibody or antibody-binding fragment thereof that has said antibody dissociation constant, KD, having a value as determined in (b) that is within tenfold of the desired concentration range of the ligand;
• and
• (d) administering to the central nervous system compartment simultaneously or sequentially and in either order at least one dose of said ligand and said antibody, or antigen-binding fragment thereof, selected in step (c), to attain the desired concentration range of the ligand as unbound free ligand in the central nervous system compartment,
• wherein the antibody-to-ligand molar ratio is approximately 1:1 or at least 2:1;
• whereby antibody buffering delays clearance of the ligand as a result of equilibrium distribution between (i) the ligand complexed to the antibody or antigen-binding fragment thereof and (ii) the unbound free ligand, such that the half-life of the ligand when administered with the antibody or antigen-binding fragment thereof is increased by at least two-fold relative to the half-life of the ligand when administered alone.

An antibody buffering method for maintaining a concentration range of a soluble small molecule or polypeptide ligand indicated for a particular disease or disorder in a subject or in a body compartment of a subject, comprising:

• (a) isolating one or a plurality of antibodies, or an antigen-binding fragment thereof, that has been generated in vivo or in vitro and that specifically binds to a small molecule or polypeptide ligand in solution, said ligand having a concentration range indicated for a particular disease or-disorder in the subject or in a body compartment in the subject;
• (b) determining, for each of the antibodies or antigen-binding fragments thereof of (a), an antibody dissociation constant, KD, for binding to the ligand;
• (c) selecting, from among the antibodies or antigen-binding fragments thereof of (a), an antibody or an antigen-binding fragment thereof that has said antibody dissociation constant, KD, having a value as determined in (b) that is within tenfold of said concentration range of the ligand;
• and
• (d) administering to the subject, or to the body compartment in the subject, simultaneously or sequentially and in either order at least one dose of said ligand and said antibody, or antigen-binding fragment thereof, selected in step (c), to attain the concentration range of the ligand as unbound free ligand in the subject or in the body compartment,
• wherein the antibody-to-ligand molar ratio is approximately 1:1 or at least 2:1;
• whereby antibody buffering delays clearance of the ligand as a result of equilibrium distribution between (i) the ligand-complexed to the antibody or antigen-binding fragment thereof and (ii) the unbound free ligand, such that the half-life of the ligand when administered with the antibody or antigen-binding fragment thereof is increased by at least two-fold relative to the half-life of the ligand when administered alone, thereby maintaining the concentration range, for the particular disease, disorder or indication, of the ligand in the subject or in the body compartment.