| abstract |
The present invention relates to an antibody having a pH-dependent binding to its antigen such that the affinity for antigen binding at physiological pH (i.e., pH 7.4) is greater than at endosomal pH (i.e. pH 6.0 or 5.5). That is, the K D or k off ratio at pH 5.5 / pH 7.4 or at pH 6.0 / pH 7.4 is greater than or equal to 2, 3, 4, 8, 10, 16, 20, 30, . These pH dependent antibodies preferentially dissociate from the antigen in endosomes. This can increase the antibody half-life compared to antibodies that have an equivalent K D at pH 7.4, but do not have pH-dependent binding, if the antigen is to undergo an antigen-mediated clearance (e.g., PCSK9). Antibodies with pH-dependent binding can reduce total antigen half-life when the antigen undergoes a reduced clearance when bound to the antibody (e. g., IL6). Antibodies with pH-dependent binding can also prolong the reduction of non-antibody bound antigen. This may be important when antagonizing the target antigens (e.g., IgE, DKKl, C5 and SOST) that are typically present at high levels. In addition, such antibodies can increase the antigen half-life when the antigen is a receptor and the receptor has an increased clearance when bound to the antibody (e. G., A GMCSF receptor). |