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Intratumoral administration of particles containing a toll-like receptor 9 agonist and a tumor antigen for treating cancer

A technology of tumor antigens and agonists, applied in medical preparations containing active ingredients, vertebrate antigen components, carrier-antigen complex structures, etc., can solve the problems of not improving the survival rate of patients with non-small cell lung cancer

Inactive Publication Date: 2019-03-15
DYNAVAX TECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the results of preclinical and phase II trials of polynucleotide TLR9 agonists are promising, systemic administration of polynucleotide TLR9 agonists did not improve survival in patients with non-small cell lung cancer when combined with chemotherapy regimens ( Schmidt, Nature Biotechnology 2007, 25:825-826)

Method used

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  • Intratumoral administration of particles containing a toll-like receptor 9 agonist and a tumor antigen for treating cancer
  • Intratumoral administration of particles containing a toll-like receptor 9 agonist and a tumor antigen for treating cancer
  • Intratumoral administration of particles containing a toll-like receptor 9 agonist and a tumor antigen for treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0286] Abbreviations: Ab (antibody); Ag (antigen); Alum (aluminum salt adjuvants, such as those sold by Brenntag Nordic A / S 85); Al(OH) 3 (aluminum hydroxide); AlPO 4 (aluminum phosphate); BMDC (bone marrow-derived dendritic cells); CC (chimeric compound); CpG (polynucleotide comprising unmethylated CG dinucleotide or its chimeric compound); CTAG1 (cancer / testis antigen 1); CTRL (control); DC (dendritic cells); ELISA (enzyme-linked immunosorbent assay); EC 50 (half maximum effective concentration); FACS (fluorescence activated cell sorting); FCS (fetal calf serum); Fic (branched copolymer of high molecular weight sucrose and epichlorohydrin, such as FICOLL sold by GE Medical); HEG ( Hexaethylene glycol); HLA (human leukocyte antigen); Hypb (hydrophobic); IFN-γ (interferon-γ); IPA (isopropanol); IT (intratumoral); mcg or μg (micrograms); MAGEA ( Melanoma antigen, family A); MW (molecular weight); MWCO (molecular weight cut-off); NaCl (sodium chloride); NaOAc (sodium acetat...

Embodiment S1

[0288] Example S1: Structures of polynucleotides and chimeric compounds

[0289] Table S1-1 shows the structures of polynucleotides and chimeric compounds, which are generally referred to herein interchangeably as CpG or CpG-ODN. The nucleotides in polynucleotides and chimeric compounds are 2'-deoxyribose polynucleotides. HEG is a hexaethylene glycol spacer part and uses 18-O-dimethoxytrityl hexaethylene glycol, 1-((2-cyanoethyl)-(N,N-isopropyl))- Phosphoramide incorporated. All internucleotide linkages and linkages between nucleic acid moieties and spacer moieties are phosphorothioate linkages.

[0290] Table S1-1: Polynucleotide (PN) and chimeric compound (CC) structures^

[0291]

[0292] ^ Unless otherwise stated, the polynucleotides and chimeric compounds of SEQ ID NO: 5, 6, 7, 8, 9, 10 and 27 include 2'-deoxy-ribose polynucleotides and the internucleotide linkages are Phosphorothioate linkage. Different compounds are given the same SEQ ID NO when the only differe...

Embodiment S2

[0294] Example S2: Structure of polypeptide antigen

[0295] Table S2-1 shows the primary structures of polypeptide antigens, which are interchangeably referred to herein as polypeptides or peptides. Polypeptides were purchased from Bio-Synthesis Inc. (Lewisville, Texas, USA) or C S Bio (Menlo Park, California, USA).

[0296] Table S2-1: Peptide structure

[0297]

[0298]

[0299] ^The hydrophobicity (Hypb) was determined using the online peptide property calculator found at "www.biosyn.com / peptidepropertycalculatorlanding.aspx" and expressed as a percentage of the full-length amino acid sequence. (polyethylene glycol) 24 / PEG 24 and Cyclohexylalanine are not included in the Hypb calculation.

[0300] The OVApep antigen includes the ovalbumin (OVA) class I epitope along with seven N-terminal amino acids from OVA to facilitate peptide excision (Cascio et al., 2001 EMBO J, 20:2357–2366) and the OVA class II epitope (Maecker et al., 1998 J Immunol, 161:6532-6536). A ...

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Abstract

The present disclosure relates to methods for treating cancer by intratumoral delivery of particles containing a Toll-like receptor 9 agonist (TLR9) and a tumor antigen, in which the TLR9 agonist is apolynucleotide or a chimeric compound thereof. The methods of the present disclosure involve injection of the particles into at least one tumor, and are effective for treating both injected and uninjected tumors of a mammalian subject. Additionally, the present disclosure provides immunogenic compositions containing the particles, as well as methods of manufacture thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 62 / 439,438, filed December 27, 2016, and US Provisional Application No. 62 / 323,622, filed April 15, 2016, which are hereby incorporated by reference in their entirety. [0003] Submit a sequence listing as an ASCII text file technical field [0004] The present disclosure relates to methods of treating cancer by intratumoral delivery of particles comprising a Toll-like receptor 9 (TLR9) agonist and a tumor antigen, wherein the TLR9 agonist is a polynucleotide or a chimeric compound thereof. The methods of the present disclosure involve injecting the particles into at least one tumor, and the methods of the present disclosure are effective for treating both injected and non-injected tumors in a mammalian subject. In addition, the present disclosure provides immunogenic compositions containing the particles and methods for their manufacture. Backgroun...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61K39/39A61K47/02A61K47/10A61K47/36A61K31/711A61P35/00
CPCA61K39/39A61K9/0019A61K9/143A61K2039/54A61K2039/55505A61K2039/55555A61K2039/55561A61K2039/64A61K45/06A61K31/7088A61P35/00A61P37/04A61P43/00A61K2239/31A61K39/4611A61K39/4622A61K39/4615A61K39/464488A61K2239/39A61K31/711A61K39/395A61K9/0014C12N15/1135A61K2039/804A61K39/0011C12Q1/6886
Inventor C·吉杜奇E·奈克R·J·麦莉S·D·奇普曼
Owner DYNAVAX TECH CORP
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