Anti-PCSK9 antibodies with pH-dependent binding characteristics

摘要

The present invention provides antibodies and antigen-binding fragments thereof that specifically bind proprotein convertase subtilisin/kexin-9 (PCSK9) with greater affinity at neutral pH than at acidic pH. The antibodies of the invention may possess one or more amino acid changes as compared to antibodies that do not exhibit pH-dependent binding properties. For example, the present invention includes anti-PCSK9 antibodies which possess one or more histidine substitutions in one or more complementarity determining regions. The antibodies of the invention, with pH-dependent binding properties, remain in circulation and exhibit cholesterol lowering activity for prolonged periods of time in animal subjects as compared to anti-PCSK9 antibodies that do not exhibit pH-dependent binding properties. The antibodies of the invention are therefore useful for treating diseases and disorders related to elevated HDL cholesterol, wherein the antibodies of the invention can be administered to a patient at a lower dose and/or with less frequent dosing as compared to antibodies that do not exhibit pH-dependent binding properties.

主权项

1. An isolated antibody or antigen-binding fragment thereof that binds human proprotein convertase subtilisin/kexin type 9 (PCSK9), wherein the acidic/neutral KD ratio for the antibody or antigen-binding fragment binding to PCSK9 at 25° C. is greater than about 12.5 as determined by surface plasmon resonance; wherein the antibody or antigen-binding fragment thereof comprises 3 heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and 3 light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3),
wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 220; wherein the HCDR2 comprises the amino acid sequence of SEQ ID NO: 222; wherein the HCDR3 comprises the amino acid sequence selected from the group consisting of SEQ ID NOs: 224 and 788; wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 802; wherein the LCDR2 comprises the amino acid sequence of SEQ ID NO: 230; and wherein the LCDR3 comprises the amino acid sequence of SEQ ID NO: 232.