ANTI-TFPI ANTIBODY VARIANTS WITH DIFFERENTIAL BINDING ACROSS PH RANGE FOR IMPROVED PHARMACOKINETICS

摘要

Antibodies are disclosed that bind to and inhibit the anti-coagulant function of TFPI and have a lower affinity for TFPI at pH 6.0 than at pH 7.4. The lower affinity at pH 6 improves circulating half-life (T½) due to reduced target mediated clearance, a process by which an antibody/antigen complex is endocytosed and trafficked to the lysosome where both components are degraded. The lower affinity at pH 6.0 results in disruption of the complex prior to lysosome targeting and allows for re-circulation of the antibody. Specific modifications to antibody binding by histidine residue substitution are disclosed along with methods of use.

主权项

1. A therapeutic composition comprises an isolated human monoclonal IgG antibody that binds specifically to human tissue factor pathway inhibitor (TFPI) and has increased plasma half-life, wherein the antibody comprises at least one histidine substitution in a CDR region in either a human heavy chain or a human light chain and antibody binds to TFPI at pH 7.4 with at least two fold higher affinity than at pH 6.0.