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Polypeptides

A sequence and identity technology, applied in the field of peptides, can solve the problems of undetectability, failure, instability, etc., and achieve the effect of inhibiting the inflammatory process

Pending Publication Date: 2022-05-10
SORRISO PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The three anti-TNF-α antibodies infliximab (trade name Remicade), adalimumab (trade name Humira) and certolizumab (or 'certolizumab (certolizumab pegol)', trade name Cimzia) is clinically used in the treatment of Crohn's disease; however, due to their inherent instability and susceptibility to Presence of inflammatory proteases and proteolytic degradation by gut microflora affect properties generally considered unsuitable for administration as oral therapeutics
However, TSLP expression was found to be undetectable in epithelial cells from 6 / 9 patients with CD
Inability of CD epithelial cells to produce S-TSLP in diseased mucosa results in failure of mechanisms that normally help maintain intestinal homeostasis by generating a non-inflammatory environment
Defects in this mechanism can induce unwanted Th1 inflammatory responses, thereby promoting the development of CD

Method used

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Examples

Experimental program
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Effect test

Embodiment 5

[0263] Example 5 describes in detail the epitope modeling work performed on the polypeptide V7R-2E9 of the present invention. This work indicates that V7R-2E9 binds to the following residues of IL-7Rα. Residues covering particularly significant regions at the interface are highlighted in bold. Residue numbering corresponds to SEQ ID NO:65.

[0264]

[0265] Therefore, in one aspect of the present invention, a polypeptide is provided that binds to an epitope on IL-7Rα (SEQ ID NO: 65), said epitope comprising IL-7Rα selected from Glu27, Ser31, Leu57, At least one residue of Val58, Glu59, Lys77, Lys78, Phe79, Leu80, Leu81, Ile82, Thr104, Lys137, Lys138, Tyr139, Lys141, His191, Tyr192 and Phe193. Suitably, the polypeptide binds to an epitope on IL-7Rα comprising at least 8, more suitably at least 15, more suitably at least all residues of IL-7Rα selected from this list.

[0266] It can be noted that certain residues of IL-7Rα cover a particularly prominent region at the inte...

Embodiment 1

[0423] Example 1: Immunization and phage library construction

[0424] Two llamas were individually immunized with soluble human recombinant IL-7Ra. Blood was collected from two llamas at different time points during immunization and tested for IL-7Rα binding and neutralization to monitor the development of an immune response against IL-7Rα. Analysis showed that only one llama developed good anti-IL-7Rα antibody titers, while the other llama failed to respond to IL-7Rα immunization. RNA isolated from leukocytes collected from responsive llamas at the end of immunization was used to generate twelve individual phage display libraries.

Embodiment 2

[0425] Example 2: Library selection with human IL-7Rα binding activity

[0426] A library selection strategy was developed to isolate ICVDs that bind to epitopes present on the extracellular domain of the IL-7Rα subunit, including ICVDs that interfere with the binding of IL-7 to IL-7R. Several approaches were used to selectively enrich for phage displaying ICVD with IL-7Rα binding characteristics and other desirable properties, including high binding affinity and resistance to enteric proteases. E. coli was infected with phage present in the eluate from the different library selections, and individual colonies were picked into master plates and propagated to generate colony cultures. Periplasmic supernatants containing selected monoclonal ICVDs were used for primary evaluation studies to identify those with desired characteristics.

[0427] From a total of 630 library-selected colonies in 8 original master plates picked to screen, a final set of 7 primary clones were selected...

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Abstract

The present invention provides, inter alia, polypeptides capable of inhibiting the binding of IL-7 and / or L-TSLP to IL-7R (IL-7R), as well as constructs and pharmaceutical compositions comprising these polypeptides.

Description

technical field [0001] The present invention relates to polypeptides capable of inhibiting the binding of IL-7 and / or L-TSLP to IL-7R, as well as constructs and pharmaceutical compositions comprising these polypeptides. The present invention also relates to nucleic acids encoding such polypeptides, methods for producing such polypeptides, cDNAs and vectors comprising nucleic acids encoding such polypeptides, host cells expressing or capable of expressing such polypeptides, and uses of such polypeptides. Background technique [0002] Autoimmune diseases of the gastrointestinal tract [0003] Autoimmune diseases of the gastrointestinal tract include inflammatory bowel diseases such as Crohn's disease (CD) and other autoimmune diseases such as eosinophilic esophagitis (EoE). Crohn's disease (also known as Crohn's syndrome) and Crohn's disease cause a variety of symptoms. It primarily causes abdominal pain, diarrhea, vomiting, and / or weight loss, but also causes complications ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C12N15/13A61K39/395A61P37/02
CPCC07K16/2866A61P37/02C07K2317/76C07K2317/565A61K2039/505A61K38/00A61P37/00A61P29/00A61P1/00A61P17/00C07K2317/92C07K2317/22C07K2317/24C07K2317/33C07K2317/569C07K16/2896
Inventor 斯科特·克罗迈克·韦斯特凯文·罗伯茨蒂姆·卡尔顿卢瓦纳·马焦雷马里恩·丘比特卢德斯·杜阿尔特马丁·西蒙斯基思·雷
Owner SORRISO PHARM INC
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