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Methods of treating cancer using anti-OX40 antibodies in combination with TLR agonists

An agonist and antibody technology, applied in the direction of antibody medical components, anti-animal/human immunoglobulin, antibodies, etc., can solve problems such as limitations

Pending Publication Date: 2022-07-08
BEIGENE BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the OX40-OX40L interaction is critical for enhancing effective antitumor immunity, blockade of OX40-OX40L limits the efficacy of these ligand-competing antibodies

Method used

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  • Methods of treating cancer using anti-OX40 antibodies in combination with TLR agonists
  • Methods of treating cancer using anti-OX40 antibodies in combination with TLR agonists
  • Methods of treating cancer using anti-OX40 antibodies in combination with TLR agonists

Examples

Experimental program
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Effect test

example 1

[0164] Example 1: Generation of anti-OX40 monoclonal antibodies

[0165] Anti-OX40 monoclonal antibodies were produced based on conventional hybridoma fusion techniques (with minor modifications) (de St Groth and Sheidegger, 1980 J Immunol Methods 35:1; Mechetner, 2007 Methods Mol Biol 378:1 ). Antibodies with high binding activity in enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell sorting (FACS) assays were selected for further characterization.

[0166] OX40 recombinant protein for immunoassays and binding assays

[0167] The cDNA encoding full-length human OX40 (SEQ ID NO: 1) was synthesized by Sino Biological (Beijing, China) based on the GenBank sequence (accession number: X75962.1). The signal peptide consisting of amino acids (AA) 1-216 (SEQ ID NO: 2) of OX-40 and the coding region for the extracellular domain (ECD) were PCR amplified and cloned into an in-house developed expression vector in which C - Terminal fusion to the Fc domain of mou...

example 2

[0179] Example 2: Cloning and sequence analysis of anti-OX40 antibodies

[0180] Murine hybridoma clones were harvested to prepare total cellular RNA using the Ultrapure RNA kit (Cat. No. 74104, QIAGEN, Germany) according to the manufacturer's protocol. First-strand cDNA was synthesized using a cDNA synthesis kit from Invitrogen (Cat. No. 18080-051), and hybridoma antibodies were performed using a PCR kit (Cat. No.: CW0686, CWBio, Beijing, China). PCR amplification of VH and VL. Antibody cDNAs for heavy chain variable region (VH) and light chain variable region (VL) were synthesized by Invitrogen (Beijing, China) based on previously reported sequences (Brocks et al., 2001 Mol Med 7:461) Cloning oligonucleotide primers. PCR products were used directly for sequencing, or subcloned into pEASY-Blunt cloning vector (Cat. No.: CB101, TransGen, China) and then sequenced by Genewiz (Beijing, China). The amino acid sequences of the VH and VL regions were deduced from the DNA sequenc...

example 3

[0186] Example 3: Humanization of murine anti-human OX40 antibody 445

[0187] Antibody Humanization and Engineering

[0188] For the humanization of Mu445, human germline IgG genes were searched for sequences with high homology to the cDNA sequences of the Mu445 variable regions by sequence alignment against the human immunoglobulin gene database in IMGT. Human IGHV and IGKV genes, which are present at high frequency in the human antibody repertoire (Glanville et al., 2009 PNAS [Proceedings of the National Academy of Sciences] 106:20216-20221) and are highly homologous to Mu445, were selected as templates for humanization.

[0189] Humanization by CDR grafting (Methods in Molecular Biology, Antibody Engineering, Methods and Protocols, Vol. 248: Humana Press), and by using in-house developed The expression vector engineered the humanized antibody to the human IgG1 wild-type form. Mutations of murine to human amino acid residues in the framework regions were guided by simulat...

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Abstract

Provided are methods of treating cancer using a non-competitive anti-OX40 antibody, and antigen binding fragments thereof, that bind to human OX40 (ACT35, CD134, or TNFRSF4) in combination with a TLR9 agonist.

Description

technical field [0001] Disclosed herein are methods of treating cancer using a combination of an antibody or antigen-binding fragment thereof that binds to human OX40 and a TLR9 agonist. Background technique [0002] OX40 (also known as ACT35, CD134 or TNFRSF4) is a type I transmembrane glycoprotein of approximately 50 KD and is a member of the tumor necrosis factor receptor superfamily (TNFRSF) (Croft, 2010; Gough and Weinberg, 2009). Mature human OX40 consists of 249 amino acid (AA) residues with 37 AA cytoplasmic tails and 185 AA extracellular domains. The extracellular domain of OX40 contains three complete cysteine-rich domains (CRDs) and one incomplete cysteine-rich domain. The intracellular domain of OX40 contains a conserved signaling-related QEE motif that mediates binding to several TNFR-associated factors (TRAFs), including TRAF2, TRAF3, and TRAF5, allowing OX40 to interact with intracellular kinases connection (Arch and Thompson, 1998; Willoughby et al., 2017)....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28
CPCA61P35/00A61P37/02A61P37/06C07K16/2878C07K2317/24C07K2317/92C07K2317/33C07K2299/00C07K2317/34C07K2317/75C07K2317/70C07K2317/732A61K2039/505A61K39/39558A61K31/555A61K33/243A61K31/513A61K2300/00
Inventor 蒋蓓蓓刘晔宋晓敏
Owner BEIGENE BEIJING CO LTD
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