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anti-IL-1r1 binding member

A member, antibody technology, applied in the direction of antibodies, anti-inflammatory agents, drug combinations, etc., can solve the problem of not clearly denying IL-1RII, non-response, etc.

Inactive Publication Date: 2015-08-19
MEDIMMUNE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, at this time it was not definitively negated that IL-1RII is able to recruit another signaling chain, although cells expressing high levels of IL-1RII have been shown to become unresponsive to IL-1β (25)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0430] Example 1 Antibody lead separation

[0431] 1.1 Screening

[0432] A large single-chain Fv (scFv) human antibody library cloned into a phage vector based on filamentous phage M13 was used for screening (106, 107). The anti-IL-1R specific scFv antibody was isolated from the phage display library using a series of selection loops on the recombinant human IL-1R-Fc that was substantially as described above (108) biotinylated. In brief, scFv-phage particles were cultured with 100 nM recombinant biotinylated human IL-1R-Fc fusion protein in solution (huIL-1R1-Fc and intrinsic biochemistry as described in Materials and Methods). Follow the manufacturer's instructions, and then capture the antigen-binding ScFv-phage on streptavidin-coated paramagnetic beads ( M-280). Then rescue the collected scFv phage particles according to the above method (109), and repeat the screening process for the second round.

[0433] A representative number of individual clones from the second round of...

Embodiment 2

[0464] Example 2: Antibody optimization

[0465] 2.1 Affinity maturity

[0466] Optimize antibody 4 and antibody 1 using affinity-based phage and ribosome display screening.

[0467] The large scFv phage library derived from the lead clone was constructed by using the standard molecular biological technology described in (115) through the variant heavy chain (V H ) And light chain (V L ) The oligosaccharide nucleic acid directed mutagenesis supplementing the defined region 3 (CDR3). The library is screened by affinity-based phage display to select variants with high affinity for human IL-1R-Fc. In the results, it is hoped that these show increased inhibitory activity of human IL-1β binding to IL-1R1. The implementation of the screening is essentially as described previously (108). In short, scFv-phage particles were cultured with recombinant biotinylated human IL-1R-Fc in solution. Then, according to the manufacturer’s instructions, the ScFv phage-binding antigen was captured on...

Embodiment 4

[0509] Example 4 provides comparable data for antibody 6 with different Fc formats, antibody 6IgG1TM (Triple Mutant234F, 235E and 331S)

[0510] Analysis materials and methods

[0511] Receptor-ligand (IL1-β) binding analysis

[0512] Receptor-ligand (Homogeneous time-resolved fluorescence method, Cis-Bio, Bedford, MA, USA) analysis method format used to inhibit HIS FLAG tag human IL-1β (internal, coliform expression; HIS FLAG IL-1β) binds to the human histidine tag (HIS) IL 1RFc fusion protein (HEK EBNA is expressed internally, as described below). more specifically Analysis can be found in Mathis (1995) Clinical Chemistry 41(9), 1391-1397.

[0513] The results of the pilot separation process were screened without dilution. The crude scFv containing the periplasmic extract was prepared into 200mM HEPES buffer pH7.4, 0.5mM EDTA and 0.5M sucrose. 5 μl of crude scFc sample was added to a 384-well low volume analysis plate (Costar 3676). Then add 2nM human HISIL 1RFc to a volume...

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PUM

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Abstract

This invention relates to binding members, especially antibody molecules, specific for interleukin 1 receptor 1 (IL-1R1). For example, isolated binding members specific for IL-1R1 which competes with IL-1 and IL-1Ra for binding to IL-1R1 and binds Il-1R1 with a KD of 10 pM or less when measured by Kinexa™. The binding members are useful for, inter alia, treatment of disorders mediated by IL-1R1 including rheumatoid arthritis, asthma and chronic obstructive pulmonary disease (COPD).

Description

Technical field [0001] The present invention relates to binding members for interleukin 1 receptor-1 (IL-1R1), especially antibody molecules. The binding members are used to treat disorders mediated by IL1-R1, including rheumatoid arthritis, asthma, and chronic obstructive pulmonary disease (COPD). The present invention also relates to a method for preparing such a binding member, a method for using the binding member of the present invention to treat a disorder mediated by IL-1R1, and the use of the binding member of the present invention in the preparation of a medicament for treating a disorder mediated by IL-1R1 . Background technique [0002] Interleukin 1 (IL-1) is a multifunctional cytokine that plays a major role in the inflammatory response during immune-mediated diseases and infections. IL-1 is produced in various cell types stimulated by bacterial products, cytokines or immune complexes. IL-1 shows autocrine and paracrine activity on various cell types, and promotes...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K16/28A61K39/395A61P11/00
CPCC07K2317/92C07K16/2866C07K2317/622C07K2317/76A61P3/10A61P9/10A61P11/00A61P11/06A61P19/02A61P19/10A61P25/28A61P29/00A61P31/18A61P35/00A61P35/02C07K16/2803C07K16/2809C07K2317/565
Inventor J·I·坎贝尔D·J·科克伦S·C·克鲁威D·K·芬奇M·A·T·格罗夫斯D·C·洛
Owner MEDIMMUNE LLC
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