ANTIBODIES WITH pH DEPENDENT ANTIGEN BINDING

摘要

The present invention relates to antibodies with 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). In other words, the KD or koff ratio at pH 5.5/pH 7.4 or at pH 6.0/pH 7.4 is more than, or ranges between, 2, 3, 4, 8, 10, 16, 20, 30, 40, or 100 or more. Such pH dependent antibodies preferentially dissociate from the antigen in the endosome. This can increase antibody half life, as compared to antibodies with equivalent KDs at pH 7.4 but with no pH dependent binding, when the antigen is one that undergoes antigen-mediated clearance (e.g., PCSK9). Antibodies with pH dependent binding can decrease total antigen half life when the antigen undergoes reduced clearance when bound to antibody (e.g., IL6). Antibodies with pH dependent binding can also prolong the decrease in antigen which is not antibody-bound. This can be important when antagonizing a target antigen typically present at high levels (e.g., IgE, DKK1, C5 and SOST). In addition, such antibodies can increase antigen half life when the antigen is a receptor and the receptor has increased clearance when bound to antibody (e.g, GMCSF receptor).

主权项

1. An antibody with pH dependent binding which specifically binds an antigen with higher affinity at pH 7.4 than at pH 6.0, wherein the KD ratio and/or the koff ratio at pH 6.0/pH 7.4 and at 25° C. is more than, or ranges between, 2, 3, 4, 8, 10, 16, or more, and wherein:
(1) the antibody with pH dependent binding has reduced plasma clearance in vivo when exposed to said antigen; (2) the antigen is both membrane bound and soluble in vivo and wherein the antibody with pH dependent binding mediates increased localization to the cell membrane receptor; (3) the amount of in vivo antigen not bound to the antibody with pH dependent binding is decreased for a prolonged time; (4) the amount of in vivo antigen bound to antibody with pH dependent binding is decreased; and/or (5) the antigen is a receptor and the receptor has reduced clearance in vivo when exposed to said antibody with pH dependent binding; as compared to an antibody without pH dependent binding that has a similar affinity for the antigen at pH 7.4, but has a comparable KD and/or koff ratio at pH 6.0/pH 7.4 and at 25° C. that is less than 2.