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Composition

A composition and drug technology, applied in the direction of drug combination, hybrid immunoglobulin, anti-animal/human immunoglobulin, etc.

Pending Publication Date: 2022-05-27
SORRISO PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, preclinical studies suggest that short-term systemic administration of IL-7R-blocking antibodies may be an effective treatment in models of gastrointestinal inflammation

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0466] Example 1: Potency of IL-7R binding polypeptides ID-A40U, V7R-2E9 and ID-A62U compared to prior art IL-7R binding polypeptides

[0467] Inhibitory potency and efficacy (maximal inhibition) of IL-7R binding polypeptides ID-A40U (SEQ ID NO: 24) and V7R-2E9 (SEQ ID NO: 25) produced in E. coli in L-7 / IL-7R neutralization ELISA In vitro assays were performed in and compared to the clinical anti-IL-7R antibody mAb829 (also known as "GSK2618960", an anti-IL-7Rα monoclonal antibody disclosed in Ellis et al. 2019).

[0468] A 7-point dilution series of ICVD was prepared in 1% BSA (at 2x assay concentration) starting at 300 nM and using a 3.2 dilution factor. The mAb829 contrast antibody was used as a positive control in the ELISA at concentrations ranging between 10 nM and 0.088 nM (2x assay concentration). Sufficient triplicate volumes were prepared for each ICVD dilution, while sufficient 2 triplicates (2 plates) were prepared for mAb829. 85 μL (or 170 μL) of each ICVD (or m...

Embodiment 2

[0482] Example 2: Biacore estimation of ICVD-IL-7R binding affinity

[0483] The binding kinetics of ID-A40U were compared to mAb829 clinical antibody in a Biacore study. IL-7Rα-His 6 - Fc was directly coated on the Biacore sensor plate (for mAb829 analysis) or captured by anti-human IgG Fc (for ICVD analysis) and the ICVD / Ab was flowed through the plate to detect binding. ID-A40U has 7.8x10 -11 Affinity of M (K D ), and mAb829 has 5.67x10 -10 Slightly lower affinity for M (K D ). The results indicated that ID-A40U showed strong binding to the antigen. ID-A62U contains E1D and R45L mutations relative to ID-A40U.

Embodiment 3

[0484] Example 3: Tolerance to Gastrointestinal Extracts

[0485] Ex vivo incubation in intestinal supernatant predicts the stability of ICVD in the gut of cynomolgus monkeys and humans. The activities of the major intestinal proteases trypsin and chymotrypsin are conserved among mammalian species, whereas proteases present in the large intestine are likely produced by host species-specific gut microflora. To generate test matrices reflecting these two environments, pooled mouse intestinal supernatants and pooled fecal supernatants were prepared. Both matrices are highly digestible for non-selected non-engineered ICVD.

[0486] Anti-TNF-α ICVD ID-38F has previously been shown to have high stability in these matrices (see WO2016 / 156465), and this property predicts that ID-38F has high stability during transport through the gut.

[0487] V7R-2E9 and ID-A40U were tested for survival in gastrointestinal extracts from both murine and human. ICVD was incubated with mouse small in...

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Abstract

Among other aspects, compositions comprising a TNF-alpha binding polypeptide and an IL-7R binding polypeptide are provided.

Description

[0001] Field of Invention [0002] The present invention relates to compositions and constructs comprising TNF-alpha binding polypeptides and IL-7R binding polypeptides. The invention also relates to nucleic acids encoding such constructs, methods of making such compositions and constructs, cDNAs and vectors comprising nucleic acids encoding such constructs, host cells expressing or capable of expressing such constructs, and such Use of compositions and constructs. [0003] Background of the Invention [0004] Tumor necrosis factor-alpha is a homotrimeric proinflammatory cytokine implicated in systemic inflammation that exists in both soluble and membrane-bound forms. TNF-α is mainly secreted by monocytes and macrophages, but also by tumor cell lines as well as CD4+ and CD8+ peripheral blood T lymphocytes and some cultured T and B cell lines. TNF-alpha is associated with inflammatory diseases, autoimmune diseases, viral, bacterial and parasitic infections, malignant and / or ne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/46C07K16/24C07K16/28A61K39/395A61P35/00A61P37/00
CPCC07K16/241C07K16/2866A61P35/00A61P37/00C07K2317/76C07K2317/565C07K2317/567C07K2317/92C07K2317/31A61K2039/505A61K2039/507C07K2317/94C07K16/244A61P29/00A61P1/00C07K2317/569C07K2319/50
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·杜阿尔特基思·雷
Owner SORRISO PHARM INC