Anti-TFPI antibody variants with differential binding across PH range for improved pharmacokinetics

Patent metadata

Field	Value
Publication number	US-9556280-B2
Application number	US-201414213278-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

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.

First claim

The invention claimed is:

1. A variant of human monoclonal IgG antibody that binds specifically to human tissue factor pathway inhibitor (TFPI), which comprises a variable light chain domain and a variable heavy chain domain, and has increased plasma half-life as compared to the parental human monoclonal IgG antibody, wherein the variant antibody further comprises:
a variable heavy chain domain defined by parental SEQ ID NO: 17, which comprises a histidine substitution selected from the group consisting of Y102H, Y32H and Y100H, and combinations thereof; and
the variant antibody binds to TFPI at pH 7.0 with at least two fold higher affinity than at pH 6.0.

2. A variant of human monoclonal IgG antibody that binds specifically to human tissue factor pathway inhibitor (TFPI), which comprises a variable light chain domain and a variable heavy chain domain, and has increased plasma half-life as compared to the parental human monoclonal IgG antibody, wherein the variant antibody further comprises:
a variable light chain domain defined by parental SEQ. ID. NO. 10, which comprises a histidine substitution selected from the group consisting of Y31H, F48H, Y49H, L27H, V45H, W90H and combinations thereof; and
the variant antibody binds to TFPI at pH 7.0 with at least two fold higher affinity than at pH 6.0.

3. The variant antibody of claim 1 , further comprising the variable light chain domain of SEQ ID NO: 10.

4. The variant antibody of claim 1 , further comprising a variable light chain domain defined by parental SEQ. ID. NO. 10, which comprises a histidine substitution selected from the group consisting of Y31H, F48H, Y49H, L27H, V45H, W90H, and combinations thereof.

5. The variant of claim 2 , further comprising the variable heavy chain domain of SEQ ID NO: 17.

6. A pharmaceutical composition comprising the variant antibody of claims 1 , 2 , 3 , 4 , or 5 and a pharmaceutically acceptable carrier.

Assignees

• Bayer Healthcare Llc

Inventors

• Murphy John
• Wang Zhuozhi
• Winter Ruth

Classifications

• C07K16/38 Primary

  against protease inhibitors of peptide structure · CPC title

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title