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Factor XI antibodies and methods of use

A coagulation factor and antibody technology, applied in the direction of anti-coagulation factor immunoglobulin, antibody, antibody medical components, etc., can solve the problem of high bleeding risk of anti-procoagulant

Active Publication Date: 2018-04-17
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Bleeding Risk Persistently High with Anticoagulants Despite Recent Improvements

Method used

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  • Factor XI antibodies and methods of use
  • Factor XI antibodies and methods of use
  • Factor XI antibodies and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0463] Human Fab Phage Library Panning

[0464] To select antibodies that recognize human factor XI, multiple panning strategies were employed. Therapeutic antibodies against different variants of the human coagulation factor XI and rabbit coagulation factor XIa catalytic domain proteins were prepared using a commercially available phage display library, Morphosys HuCAL The library was used as a source of antibodies to select clones that bind to coagulation factor XI. Phagemid libraries are based on concept (Knappik et al., 2000, J Mol Biol 296:57-86) and employs CysDisplay displaying Fabs on the surface of phage TM technology (WO01 / 05950). For the isolation of anti-Factor XI antibodies, a liquid phase panning strategy was used.

[0465] Cross-reactivity analysis

[0466] Purified Fabs were tested in ELISA for binding to different variants of human Factor XI (Factor XI, Factor XIa and Factor XIa catalytic domain) and rabbit Factor XIa catalytic domain biotinylated prote...

Embodiment 2

[0470] combine data

[0471] Surface plasmon resonance (SPR) analysis of the catalytic domain of FXI.

[0472] via BIACORE TM T200 Optical Biosensor Based on Surface Plasmon Resonance (BIACORE TM , GE Healthcare, Uppsala) for SPR assay. S series sensor chip (CM5), fixation kit and regeneration buffer were purchased from GE Healthcare (Uppsala). Two different assay settings were performed depending on the ligand format IgG or Fab. First, the surface was activated by N-hydroxysuccinimide (NHS) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC). NOV1401-Fab was covalently attached to the activated dextran matrix on the CM5 chip by standard amine coupling methods (GE Healthcare, Uppsala). For NOV1401-IgG, a capture assay was performed and goat anti-human IgG-Fc antibody (JIR) was immobilized on the chip at 14000 RU. The remaining reactive surface groups were inactivated with ethanolamine (EA). Reference cells without immobilized ligand were prepared and ...

Embodiment 3

[0487] Biochemical Assays: Inhibition of FXIa Using Fluorescent Peptides as Substrates in Activity Assays

[0488] The activity of human FXIa (Kordia Life Science NL, Cat. No. HFXIa 1111a) was monitored by a fluorescently labeled peptide with the sequence D-Leu-Pro-Arg*Rh110-D-Pro (Cat. No. BS-2494; Biosyntan GmbH, Berlin, Germany ) cracking is determined. In the substrate sequence written above, * indicates scissile bond, D-Leu: D-leucine, Pro: proline, Arg: arginine, Rh110: rhodamine 110, D-Pro: D -proline). FXIa-mediated cleavage of the scissile bond of the peptide substrate resulted in an increase in the fluorescence intensity of rhodamine 110 when excitation and emission wavelengths of 485 nm and 535 nm were used, respectively. Fluorescence intensity was measured continuously at room temperature (RT) using a microtiter plate reader Safire2 (TECAN, Maennedorf, Switzerland). Assay buffer contains 50mM HEPES (pH 7.4), 125mM NaCl, 5mM CaCl 2 and 0.05% (w / v) CHAPS. In the...

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Abstract

The present invention relates to monoclonal antibodies and antigen binding fragments thereof that bind to human Factor XI and activated Factor XI ("Factor XIa"), and pharmaceutical compositions and methods of treatment comprising the same.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 184,955, filed June 26, 2015, and U.S. Provisional Application No. 62 / 341,568, filed May 25, 2016, each of which is hereby incorporated in its entirety Incorporated herein by reference. [0002] This application contains a Sequence Listing, which has been filed electronically in ASCII format, and is hereby incorporated by reference in its entirety. This ASCII copy was created on June 23, 2016, named "PAT056955_SL.txt" and 45,685 bytes in size. Background technique [0003] Thrombosis is the formation of blood clots inside blood vessels after experiencing a combination of genetic and acquired risk factors known as thrombophilia or hypercoagulable states. Vascular wall damage, stasis, increased platelet reactivity, and activation of coagulation factors are some of the basic features of thrombus formation. Thrombosis can occur in the venous and arterial circulation and can lead to the occurrence o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/36
CPCC07K16/36A61P9/10A61P7/02C07K2317/565C07K2317/76A61K2039/505C07K2317/21C07K2317/33C07K2317/34C07K2317/55C07K2317/92C07K16/40A61K39/3955C07K2317/56A61K45/06C12N15/63
Inventor J·埃德尔S·埃韦特U·哈西佩Y·赫德尔L·M·迈尔S·梅尔科N·希尔林
Owner NOVARTIS AG
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