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EGFR binding molecules

A technology of binding sites and antibody molecules, applied in drug combinations, organic active ingredients, antibody medical ingredients, etc., can solve problems such as overall survival and progression-free survival

Pending Publication Date: 2019-03-15
F STAR THERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Randomized phase II study of gefitinib alone or in combination with fencratuzumab in Asian patients with previously untreated lung adenocarcinoma with or without EGFR mutation failed to demonstrate improved overall survival or progression-free survival
[0019] HuL2G7 (formerly TAK-701) is a humanized monoclonal antibody that potently neutralizes HGF and was tested in a phase I study for advanced non-hematological malignancies, but does not appear to have advanced to further development

Method used

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  • EGFR binding molecules
  • EGFR binding molecules
  • EGFR binding molecules

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] Example 1 - Preparation of Anti-EGFR Antigen Binding Fcs (Fcab)

[0161] EGFR-specific Fcabs were selected from yeast-displayed Fcab libraries by fluorescence-activated cell sorting (FACS) and from phage-displayed Fcab libraries by magnetic bead capture as described below.

[0162] Primary selection of anti-EGFR Fcabs from a yeast library using FACS

[0163] A method for selecting antigen-specific Fcabs by FACS from a yeast display Fcab library is described in WO 2009 / 132876. A library of clones expressing Fcabs on the surface of yeast cells was incubated with 300 nM biotinylated EGFR extracellular domain. Cells were then stained with Streptavidin-Allophycocyanin (APC) (BD Bioscience, 349024) to separate antigen-binding yeast cells based on fluorescent signal using a high-speed cell sorter (BD Bioscience, FACSAria). This selection procedure was repeated several times to enrich for a sufficiently pure population of antigen-binding yeast cells. Streptavidin-APC and a...

Embodiment 3

[0176] Example 3 - EGFR-specific Fcabs bind to epitopes on EGFR other than cetuximab

[0177] Surface plasmon resonance (SPR) was used to determine whether EGFR-specific Fcabs FS1-60, FS1-65 and FS1-67 competed with a known anti-EGFR antibody, cetuximab (Merck), for binding to EGFR.

[0178] BIAcore 3000 (GE healthcare) was used to determine whether EGFR-specific Fcabs FS1-60, FS1-65 and FS1-67 were likely to bind to human EGFR-coated chips saturated with cetuximab (CX) and vice versa.

[0179]A streptavidin chip (SA chip) (GE Healthcare BR-1000-32) was coated with 200RU of biotinylated human EGFR extracellular domain (ECD). Experiments were performed in HBS-P buffer using a flow rate of 20 μl / min (GE Healthcare) and the EGFR surface was regenerated by passing 50 mM NaOH three times at 50 μl / min for 12 s. The first EGFR-binding compound (EGFR-specific Fcab or cetuximab) was injected at 20 μl / min for 4 minutes, followed by the second EGFR-binding compound (cetuximab or EGFR-...

Embodiment 4-E

[0183] Example 4 - Binding affinity of EGFR-specific Fcabs to human and mouse EGFR

[0184] The binding affinity of EGFR-specific Fcabs to human and mouse EGFR was determined using SPR. For affinity measurement, a BIAcore 3000 instrument (GE healthcare) was used and the SA chip was coated with 200 or 1000 RU of biotinylated human (in-house) or mouse (Sino Biological) EGFR extracellular domain. A serial concentration of Fcab (1-1000 nM) in HBS-P buffer (GE Healthcare) was injected at 20 μl / min for 2.5 minutes to measure association rates. HBS-P buffer was then injected for 15 minutes to measure the off-rate. 50 mM NaOH was used twice at 50 μl / min for 10 seconds to regenerate the EGFR surface. Binding affinities (K D ). The results show that EGFR-specific Fcabs bind to human and mouse EGFR with binding affinities between 0.7–6.0 nM (see Table 3).

[0185] Table 3: Binding affinity of EGFR-specific Fcabs to human and mouse EGFR (K D )

[0186] Fcab

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Abstract

The application relates to specific binding members which bind the human epidermal growth factor receptor (EGFR). The specific binding members preferably comprise an EGFR antigen-binding site which may be located in two or more structural loops of a CH3 domain of the specific binding member. The specific binding members are expected to find application in the treatment of cancers expressing EGFR.

Description

[0001] related application [0002] This case claims priority from GB 1612520.5 filed on 19 July 2016, the contents of which are hereby incorporated by reference in their entirety. technical field [0003] The present invention relates to specific binding members that bind human epidermal growth factor receptor (EGFR). The specific binding member preferably comprises an EGFR antigen binding site, which may be located in two or more structural loops of the CH3 domain of the specific binding member. The specific binding members of the invention are useful in the treatment of cancers expressing EGFR. Background technique [0004] Epidermal growth factor receptor (EGFR; also known as ErbB-1 and HER1) is a cell surface receptor for a member of the epidermal growth factor family (EGF-family) of extracellular protein ligands. EGFR is a large, monomeric glycoprotein with a single transmembrane region and a cytoplasmic tyrosine kinase domain flanked by a noncatalytic regulatory re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C07K16/22A61K39/395A61K31/517
CPCA61K39/39558A61K31/517C07K16/22C07K16/2818A61K2039/505A61K2039/507C07K2317/31C07K2317/33C07K2317/524C07K2317/526C07K2317/53C07K2317/73C07K2317/732C07K2317/76C07K2317/77C07K2317/92C07K2317/94C07K2318/20C07K16/2863A61P11/00A61P35/00A61K2300/00A61K31/519C07D487/04C07B2200/13A61K47/6845A61K47/6813C07K16/468C07K2317/56C07K2317/565
Inventor 密里班·图纳梁健美孙海军梅勒妮·麦德卡夫沙米·艾萨克
Owner F STAR THERAPEUTICS LTD
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