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Factor XI antibodies and methods of use

A technology of antibodies and fragments, applied in the direction of anticoagulant immunoglobulin, antibodies, antibody medical components, etc., can solve the problem of high bleeding risk of anticoagulants

Pending Publication Date: 2022-04-22
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] 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

[0466] Human Fab phage library selection

[0467] In order to select antibodies that recognize human coagulation factor XI, multiple emoticoning strategies were used. Therapeutic antibodies against different variants of human clotting factor XI and rabbit clotting factor XIa catalyzed domain proteins are used in commercially available phage display libraries known as Morphosys HuCAL Libraries are selected as antibody sources to bind to clonal cloning of coagulation factor XI. The bacteriophage granule library is based Concept (Knappik et al., 2000, J Mol Biol 296:57-86) and using CysDisplay showing Fab on the phage surface TM Technology (WO01 / 05950). For the isolation of anticoagulant factor XI antibodies, a liquid phase emoting strategy was used.

[0468] Cross-reactivity analysis

[0469] Binding of purified Fab to different variants of human coagulation factor XI (coagulation factor XI, coagulation factor XIa and coagulation factor XIa catalytic domain) and rabbit coagulation...

Embodiment 2

[0473] Combine data

[0474] Surface plasmon resonance (SPR) analysis of FXI catalytic domains.

[0475] Via BIACORE TM T200 Optical Biosensor (BIACORE) based on surface plasmon resonance TM, GEHealthcare, Uppsala) for SPR assay. The S Series sensor chip (CM5), fixation kit, and regeneration buffer were purchased from GE Healthcare (Uppsala). Two different analyses are set depending on the ligand form IgG or Fab. First, the surface is activated by N- hydroxysuccinimide (NHS) and N- (3-dimethylaminopropyl)-N-ethylcarbonized diimide hydrochloride (EDC). Nov1401-Fab is covalently connected to the activated dextran matrix on the CM5 chip by a standard amine coupling method (GE Healthcare, Uppsala). For NOV1401-IgG, capture analysis was performed and goat anti-human IgG-Fc antibody (JIR) was fixed to the chip at 14,000 RU. Inactivate the remaining active surface groups with ethanolamine (EA). Prepare reference cells without fixed ligands and equilibrate the system with 1×HBS-EP+ buffe...

Embodiment 3

[0490] Biochemical analysis: Fluorescent peptides are used as substrates to inhibit FXIa in activity analysis

[0491]The activity of human FXIa (Kordia Life Science NL, catalog number HFXIa 1111a) was determined by monitoring the lysis of fluorescently labeled peptides with the sequence D-Leu-Pro-Arg*Rh110-D-Pro (product number BS-2494; Biosyntan GmbH, Berlin, Germany). In the substrate sequence written above, * indicates easy-to-cut bonds, D-Leu: D-leucine, Pro: proline, Arg: arginine, Rh110: rhodamine 110, D-Pro: D-proline). When using excitation and emission wavelengths of 485 nm and 535 nm, respectively, the FXIa-mediated lysis of the peptide substrate's easy-to-cut bonds leads to an increase in the fluorescence intensity of rhodamine 110. Fluorescence intensity was continuously determined at room temperature (RT) using the microtiter plate reader Safire2 (TECAN, Maennedorf, Switzerland). The analysis buffer contains 50 mM HEPES (pH 7.4), 125 mM NaCl, and 5 mM CaCl 2 and 0.0...

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Abstract

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

Description

[0001] This application is a divisional application of The Chinese Patent Application No. 201680048982.9 (PCT / IB2016 / 053790) with the title of invention "Coagulation Factor XI Antibody and Method of Use" is filed on June 24, 2016. [0002] This application claims the interests of U.S. Provisional Application No. 62 / 184,955 filed on June 26, 2015 and U.S. Provisional Application No. 62 / 341,568 filed on May 25, 2016, each of which is hereby incorporated herein by reference in full. [0003] The present application comprises a sequence listing, which has been filed electronically by ASCII form, and the entire contents of which are incorporated herein by reference. This ASCII replica was produced on June 23, 2016, named "PAT056955_SL.txt" and is 45,685 bytes in size. Background [0004] Thrombosis refers to the formation of thrombosis inside a blood vessel after undergoing a combination of hereditary and acquired risk factors called a predisposition to thrombosis or a state of hype...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/36C12N15/13A61K39/395A61K45/06A61P9/10A61P7/02
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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