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Compounds and methods for treating inflammatory diseases

a technology of iga antibodies and compounded igas, which is applied in the field of monoclonal secretory iga antibodies, can solve the problems of difficult undesirable use of animal-derived antibodies and polyclonal antibodies, and the inability to purify several other chromatographic media. the potential of purification of carorx antibodies is small

Inactive Publication Date: 2015-01-08
SYNTHON BIOPHARMACEUTICALS BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The uses of animal-derived antibodies and polyclonal antibodies, however, are undesirable.
Apparently, the CaroRx antibody was difficult to purify; the affinity of Protein A for the murine Ig domain was too low and protein G was necessary for sufficient affinity chromatography.
Furthermore, the article states that several other chromatographic media had shown little potential as purification steps for the hybrid sIgA-G from tobacco leaf extracts.

Method used

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  • Compounds and methods for treating inflammatory diseases
  • Compounds and methods for treating inflammatory diseases
  • Compounds and methods for treating inflammatory diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Stable Expression of Anti-IL-12 / 23 Secretory Protein Based on Ustekinumab (UKB-SA1) in Lemna

[0126]a) Construction of Vectors

[0127]Synthetic genes were designed for each of the 4 different protein chains of an anti-p40 (anti-IL-12 / 23) secretory IgA. The amino acid sequence of the heavy chain consisted of the rice α-amylase secretion signal (SEQ ID NO:17) joined to the N-terminal amino acid of the variable part of the heavy chain of anti-IL12 / 23 IgG1 antibody Ustekinumab (Stelara®, CAS number 815610-63-0, SEQ ID NO:1) which in turn is joined to the N-terminal amino acid of the constant part of a human IgA1 heavy chain (SEQ ID NO:5). The amino acid sequence of the light chain consisted of the rice α-amylase secretion signal (SEQ ID NO:17) joined to the N-terminal amino acid of the light chain sequence of ustekinumab (CAS number 815610-63-0), which combines an anti-p40 (anti-IL-12 / 23) binding variable part (SEQ ID NO:2) with a human κ-light chain constant part (SEQ ID NO:9). The SC-cha...

example 2

Isolation and Purification of UKB-SA1 and UKB-SA1g0 Secretory IgA Antibody from Lemna

[0136]Biomass from transgenic Lemna expressing UKB-SA1 or UKB-SA1g0, having variable regions that are the amino acid sequence of the variable regions (antigen binding regions) of ustekinumab, was homogenized in 50 mM Sodium phosphate, 0.3M Sodium chloride, buffer pH 7.4, at a buffer to tissue ratio of 4:1. An acid precipitation step was performed on the crude extract to remove the enzyme ribulose bis-phosphate carboxylase (RuBisCo) and other plant proteins by adjusting the extract to pH 4.5 using 1M Sodium acetate, pH 2.5. The precipitate was removed by centrifugation of the material at 14,000×g for 30 minutes at 4° C. The supernatant was adjusted to pH 7.4 and filtered to 0.22 μm prior to IMAC chromatography.

[0137]IMAC purification: A chelating Sepharose FF (GE Healthcare prod. Nr. 17-0575-01) column was prepared according to manufacturer instructions (28-4047-39 AC). The column was charged with 3...

example 3

Binding of UKB-SA1 and UKB-SA1g0 to IL12

[0146]The binding of purified anti-IL-12 / 23 SIgA, with variable regions taken from ustekinumab and produced in Lemna as in Examples 1 and 2, to IL-12 was determined. The binding of both UKB-SA1 and UKB-SA1g0 products were determined in comparison to ustekinumab (STELARA®) and colostral SIgA. Plates were coated with IL-12 (Abcam, AB52086) 1 μg / ml. Detection of bound UKB-SA1 / UKB-SA1g0 (secretory IgA) and ustekinumab (IgG1) antibodies was performed using a 1:1500 fold dilution of anti human kappa chain antibody (Abbiotec, cat. no. 250987), 100 μl per well, for one hour at RT, washing 3 times, 30 seconds with 200 μl PBS / 0.05% Tween with shaking, followed by incubation with a 1:1500 fold dilution of donkey anti mouse HRP conjugated (Emelca biosciences, MS3001), 100 μl per well, for one hour at RT.

[0147]The UKB-SA1, UKB-SA1g0 and ustekinumab antibodies all bound with high affinity to IL-12 under the conditions of this assay. For UKB-SA1 and UKB-SA1g...

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Abstract

A monoclonal secretory IgA antibody, which binds to and neutralizes human p40 (the p40 subunit of IL-12 and IL-23). The secretory antibody is useful in treating a variety of inflammatory conditions in humans.

Description

[0001]This application claims the benefit of priority under 35 U.S.C. §119(e) from U.S. provisional patent application Ser. No. 61 / 576,727, filed Dec. 16, 2011, and Ser. No. 61 / 576,922, filed Dec. 16, 2011; the entire contents of each provisional application being incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to monoclonal secretory IgA antibodies, which bind to and neutralize human p40 (the p40 subunit common to IL-12 and IL-23). The antibodies are useful in treating inflammatory diseases in humans, including by oral administration.BACKGROUND OF THE INVENTION[0003]Inflammation represents a key event of many diseases, such as psoriasis, inflammatory bowel diseases, rheumatoid arthritis, asthma, multiple sclerosis, atherosclerosis, cystic fibrosis, and sepsis. Inflammatory cells, such as neutrophils, eosinophils, basophils, mast cells, macrophages, endothelial cells, and platelets, respond to inflammatory stimuli and foreign substances by ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/24
CPCC07K16/244C07K2317/565C07K2317/41A61K2039/505C07K2317/76A61K2039/54A61P1/00A61P17/06A61P19/02C07K16/241C07K2317/13C07K2317/24A61K9/0053A61K39/00C12N15/8258
Inventor ARIAANS, GERARDUS JOSEPH ANDREASVAN DALEN, FRANSNOLAN, DECLAN THOMAS
Owner SYNTHON BIOPHARMACEUTICALS BV
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