Anti-il-1r1 single domain antibodies and therapeutic uses

An interleukin and antagonist technology, which can be used in respiratory diseases, receptors/cell surface antigens/cell surface determinants, allergic diseases, etc., and can solve problems such as failure to meet primary endpoints

Inactive Publication Date: 2008-02-27
DORMANTIS LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, other agents that bind IL-1R1, such as the anti-IL-1R1 antibody AMG 108 (Amgen), have failed to meet the primary endpoints in clinical studies

Method used

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  • Anti-il-1r1 single domain antibodies and therapeutic uses
  • Anti-il-1r1 single domain antibodies and therapeutic uses
  • Anti-il-1r1 single domain antibodies and therapeutic uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0246] Example 1. IL-1R1 Immunoglobulin Variable Domain Antagonists

[0247] method

[0248] selection and filtering

[0249] For primary selection, the 4G-K2 library of VK dAbs was panned against the IR1-Fc fusion protein (Axxora, Nottingham, UK). Domain antibodies selected from the primary screen were subjected to three further rounds of screening. The first round was carried out with protein G coated with magnetic beads (Dynal, Norway); the second round was carried out with anti-human IgG beads and 10 nMIL-1R1-Fc (Novagen, Merck Biosciences, Nottingham, UK); the third round was carried out with Protein G beads and 1 nM IL-1R1-Fc were performed. (See Henderikx et al, Selection of antibodies against biotinylated antigens. Antibody Phage Display: Methods and protocols, Ed. O'Brien and Atkin, Humana Press (2002).) Elution was performed at each stage with 1 mg / ml trypsin-PBS . For the affinity maturation screen, the method described above was used with the following modif...

Embodiment 2

[0275] Example 2. IL-1R1 Antagonist Subchronicity of COPD in C57BL / 6 Mice valid within the model

[0276] In this study, IL-1R1 antagonists (and half-life-extending fusion proteins including IL-1ra and binding to mouse serum albumin) were administered alone or in combination with TNFR1 at intervals starting 24 hours before initial tobacco smoke exposure. 48 hours intraperitoneal injection. The effects of tobacco smoke-induced changes in indices of lung inflammation induced by 11 consecutive days of tobacco smoke exposure were examined 24 hours after the final exposure. This result demonstrates that IL-1R1 antagonists are effective in the mouse model. ENBREL(R) (etanercept; Immunex Corporation), which binds TNF and thus antagonizes TNFR1, was used as a comparator.

[0277] Test compound 1: ENBREL(R) (etanercept; Immunex Corporation)

[0278] Test compound 2: IL-1ra / anti-S A dAb (IL-1ra fused to DOM7m16)

[0279] Test compound 3: a mixture of PEG DOMIm (anti-TNFR1 dAb in...

Embodiment 3

[0299] Example 3. Local Administration of Immunoglobulin Variable Domains to Lung Tissue

[0300] In this study, a domain antibody that binds egg lysozyme (V H ) for topical administration to lung tissue by intranasal administration. This result demonstrates that domain antibodies can be delivered locally to a lung tissue model.

[0301] method

[0302] Female mice (C57BL / 6) were all bred and undocumented specific organisms (16-20 g) (Charles River) were bred and housed in groups of 5 in ventilated, solid bottomed, poplar sawdust beds (IVC). The environment (airflow, temperature and humidity) inside the cages was controlled by an IV system (Techniplast). The domain antibody HEL4 binds the V of egg lysozyme H . (See, Jespers et al. J. MoI. Biol., 337:893-903 (2004). The HEL-4 monomer containing the HA-tag for detection was diluted with 20 mM sodium citrate and 100 mM NaCl at pH=6.0. Mice were lightly anesthetized (isofluorane / O 2 ) and slowly drop 50 microliters of dAb...

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Abstract

Disclosed here is the application of interleukin-1 type I receptor (IL-1R1) in the preparation of medicines for treating, preventing or inhibiting pneumonia or respiratory diseases. In some embodiments of the described inventions, the medicament is for local administration to lung tissue. Also disclosed herein are methods of treating pneumonia or respiratory disease.

Description

[0001] related application [0002] This application is a continuation in part of International Application No. PCT / GB2005 / 002163, which designated the United States and was filed on May 31, 2005, and the claims of this application were filed on December 2, 2004 US Provisional Application No. 60 / 632,361; and this application claims UK priority to Application No. 0521621.3 filed October 24, 2005 under 35 USC § 119 or 365. The entire teaching of the above application is hereby incorporated by reference in its entirety. Background technique [0003] Many agents with therapeutic or diagnostic potential are not possible for in vivo use. A number of agents with in vivo serum half-lives sufficiently long to produce therapeutic or diagnostic efficacy are unable to penetrate tissues or organs to produce the desired therapeutic or diagnostic effect at the intended location. Small amounts of agents can enter tissues and organs, but often have short in vivo serum half-lives and are rapi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/44A61K47/48A61P11/00
CPCC07K16/2866C07K2318/20C07K2317/31C07K2319/00C07K2317/569C07K14/70578A61K39/3955C07K16/18C07K2318/10C12N15/62C07K2319/31A61K47/48561A61K47/48284A61K47/48415C07K14/7155C07K2317/626A61K47/48215A61K2039/555A61K47/48538C07K16/44A61K47/60A61K47/643A61K47/6811A61K47/6843A61K47/6849A61P11/00A61P11/06A61P35/00A61P37/06A61P37/08A61P43/00A61K47/50
Inventor 鲁德·M·德威尔德特菲利普·D·德鲁兰·M·汤姆林森玛丽·菲特茨杰拉尔德克雷格·福克斯斯蒂文·霍尔姆斯
Owner DORMANTIS LTD
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