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Antibodies against poliovirus receptor (PVR) and uses thereof

A technology of antibody and humanized antibody, which is applied in the direction of antibodies, antiviral agents, receptors/cell surface antigens/cell surface determinants, etc., and can solve problems such as reducing viability

Pending Publication Date: 2022-05-13
NECTIN THERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, blocking PVR on tumor cells is expected to reduce their viability

Method used

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  • Antibodies against poliovirus receptor (PVR) and uses thereof
  • Antibodies against poliovirus receptor (PVR) and uses thereof
  • Antibodies against poliovirus receptor (PVR) and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-N56

[0239] Example 1 - N56E and N56D variants have improved affinity for PVR binding

[0240]The variable region of the chimeric anti-PVR antibody 5B9 disclosed in WO2017149538 carries a deamidation sequence (asparagine-glycine) in the light chain CDR2 (WASSRHNG, SEQ ID NO: 17). Seven chimeric variants were generated by introducing a point mutation at residue asparagine N56. To assess the binding affinity of N56 substitution variants, wild-type (WT) and substitution variant IgG4 (S241P) monoclonal antibodies were immobilized on protein A capture chips. Binding of the analyte PVR conjugated to a histidine tag (PVR-HIS, Sino Cat. no. 10109-H08H) was tested. Dilution range: 5-point doubling dilution, from 50nM to 3.125nM. Conditions used: Instrument: Biacore T200 (serial number 1909913) running Biacore T200 evaluation software V2.0.1. Running buffer: HBS-P+, 300 mM NaCl, 1 mg / ml BSA. Flow rate: 30 μl / min. Association: 350s, dissociation: 800s. Regeneration: 10 mM Glycine pH 1.5...

Embodiment 2

[0241] Example 2 - N56E and N56D variants improve cross-reactivity to monkey PVR binding.

[0242] Binding of N56 substitution variant antibodies to cell-associated human PVR (protein id: Q92692) and chlorocebus PVR (African green monkey, protein id: UniProtKB-P32506) was examined. Figure 2A Relative binding of all variants added at saturating concentrations (10 ug / ml) to NCI-H1975 cells expressing human PVR is depicted. Figure 2B Relative binding of all variants added at saturating concentrations (10 ug / ml) to Vero cells expressing Vero cells PVR is depicted. For detection, goat anti-human-647 antibody (Jackson ImunomeResearch 109-606-088) was used at a 1:250 dilution. Ab cell binding was analyzed by FACS. The fold change was calculated by dividing the MFI of each variant by the MFI of the parental antibody (K0). A significant (>25%) increase in cross-reactivity was observed for the N56E and N56D variants.

Embodiment 3-N56

[0243] Example 3 - N56E and N56T variants improve NK activation

[0244] NK cells from healthy donors were incubated in the presence of selected N56 substitution variants and the target breast cancer cell line (MDA-MB-231) at an E:T ratio of 2:1 for 2 hours at 37°C. NK cell activation was measured by inducing CD107a surface expression and the fold change (Y-axis) of each variant over control IgG was calculated. All monoclonal antibodies were used at 600 pM (0.09 ug / ml). (by two-tailed student t-test, *p image 3 As shown, the N56E and N56T variants showed improved NK activation compared to KO, as manifested by increased expression of CD107a.

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PUM

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Abstract

The present invention provides humanized antibodies and antigen binding fragments thereof that bind to human poliovirus (PVR). The antibodies can be used to treat tumors or cancers.

Description

[0001] field of invention [0002] The present invention belongs to the field of immunotherapy and relates to a humanized antibody specifically binding to human poliovirus receptor (PVR), comprising a specific set of CDR and framework sequences. Also included are pharmaceutical compositions comprising these humanized antibodies and uses thereof. [0003] Background of the invention [0004] Poliovirus receptor (PVR), also known as CD155, is a transmembrane glycoprotein involved in mediating cell adhesion to extracellular matrix molecules. It has previously been described as a tumor antigen and as a potential target for therapeutic intervention due to its upregulation in neuroectodermal carcinomas including glioblastoma multiforme, medulloblastoma and colorectal cancer (Solecki et al., J. Biol. Chem. 2002, 277:25697-700) and pancreatic cancer (Nishiwada et al., Anticancer Res. 2015, 35(4):2287-97). It is also known that PVR enhances serum-induced activation of Ras-Raf-MEK-ERK ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C12N15/13C12N5/10A61K39/395A61P35/00A61P35/02A61P37/02A61P43/00A61P27/02A61P31/14A61P29/00
CPCC07K16/2896C12N5/0682A61P35/00A61P35/02A61P37/02A61P43/00A61P27/02A61P31/14A61P29/00C07K2317/56C07K2317/565C07K2317/76C07K2317/30C07K2317/73C07K2317/92C07K2317/24C12N2510/00A61K2039/505Y02A50/30C07K14/7051C07K2317/622
Inventor 菲利普·阿尔伯茨阿里夫·杰萨约翰·弗兰松亚赞·吉梅安乔安妮·休姆皮恩卡斯·茨克尔曼
Owner NECTIN THERAPEUTICS LTD
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