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Improved human herpesvirus immunotherapy

A herpes virus and immune response technology, applied in the field of recombinant proteins, can solve the problems of not showing clinical efficacy and not entering clinical practice

Pending Publication Date: 2015-09-16
COUNCIL OF THE QUEENSLAND INST OF MEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these approaches have not shown convincing clinical efficacy and thus have not entered clinical practice

Method used

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  • Improved human herpesvirus immunotherapy
  • Improved human herpesvirus immunotherapy
  • Improved human herpesvirus immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0210] Purification and immunogenicity of CMV polyepitope protein

[0211] Materials and methods

[0212] Construction of CMV multi-epitope vector

[0213] A series of CMV polyepitope inserts were designed to encode multiple HLA class I-restricted T-cell epitopes from five different antigens (pp65, IE-1, pp50, pp150 and gB). These polyepitopic sequences encode 13, 14, 15 or 20 different HLA class I-restricted CD8 + Epitopes (see Table 1).

[0214] Multi-epitope sequences were designed in such a way that each epitope sequence was preceded by a proteasome-released amino acid sequence (AD or K or R) and a TAP recognition motif ( RIW , QUR , NIW or NQY). In addition, a hexahistidine tag was inserted at the C-terminus of each polyepitopic protein to allow purification using a nickel-nitrilotriacetic acid (Ni-NTA) column. The amino acid sequence of each construct was translated into a DNA sequence based on codon utilization in Escherichia coli, and the insert was construc...

Embodiment 2

[0248] Immunogenicity of Adjuvanted CMV Polyepitope Proteins

[0249] Materials and methods

[0250] CMV multi-epitope vaccine formulation with MPL and CpG ODN1826

[0251] The CMV polyepitope vaccine was formulated by mixing 20 μg of CMVpoly, CMVpoly-PL or CMVpoly-PTL with 25 μg of MPL (TLR4 agonist) and 50 μg of CpG ODN1826 (TLR9 ​​agonist) per dose in a volume of 100 μL. TLR agonists were purchased from InvivoGen (San Diego, CA, USA).

[0252] mouse immunization

[0253] HHD 1 mice containing human HLA-A*0201 with disrupted mouse MHC class I were bred and maintained under specific pathogen-free conditions under QIMR. All protocols were in compliance with the QIMR Animal Ethics Committee. At least 5 (M1-5) six- to eight-week-old mice per group were immunized subcutaneously (s.c.) at the base of the tail using the CMV multi-epitope vaccine formulated with the specific adjuvant combinations described above. Mice were boosted on day 21 with the same vaccine formulation and...

Embodiment 3

[0278] Immunogenicity of EBV polyepitope proteins combined with adjuvants

[0279] Materials and methods

[0280] Construction of EBV multi-epitope construct

[0281] EBV polyepitopes were designed to encode multiple HLA class I-restricted T cell epitopes from nine different antigens (BMLF1, BRLF1, BZLF1, LMP2, LMP2A, EBNA1, EBNA3A, EBNA3B and EBNA3C). Epitope HLA restrictions, amino acid sequences and amino acid positions of these epitopes are listed in Table 3, and in Figure 13 Illustration in A.

[0282] The polyepitope sequences were designed in such a way that each epitope sequence was preceded by a proteasome released amino acid sequence (AD or K or R), and a hexahistidine tag insert at the C-terminus of each polyepitope protein to allow purification with a nickel-nitrilotriacetic acid (Ni-NTA) column. The amino acid sequence of each construct was translated into a DNA sequence according to the codon utilization of Escherichia coli, and then the insert was construct...

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Abstract

An isolated protein comprises respective amino acid sequences of each of a plurality of CTL epitopes from two or more different herpesvirus antigens and further comprises an intervening amino acid or amino acid sequence between at least two of said CTL epitopes comprising proteasome liberation amino acids or amino acid sequences and, optionally, Transporter Associated with Antigen Processing recognition motifs. The isolated protein is capable of rapidly expanding human cytotoxic T lymphocytes (CTL) in vitro and eliciting a CTL immune response in vivo upon administration to an animal as an exogenous protein. Typically, the isolated protein comprises no more than twenty (20) CTL epitopes derived from cytomegalovirus and / or Epstein-Barr virus antigens.

Description

technical field [0001] The present invention relates to human herpes virus immunotherapy. In particular, the present invention relates to recombinant proteins comprising multiple cytotoxic T cell epitopes derived from various human cytomegalovirus (CMV) or Epstein-Barr virus (EBV) antigens, wherein when It can elicit cytotoxic T lymphocyte immune response when used in immunotherapy, but is not limited thereto. Background technique [0002] Epstein-Barr virus exists at extremely high rates, with more than 90% of adults showing some signs of exposure. EBV also persists as a lifelong latent infection and can be asymptomatic. However, EBV can cause mononucleosis, also known as glandular fever, which causes significant morbidity in some individuals. EBV can be associated with several autoimmune diseases such as lupus, rheumatoid arthritis and multiple sclerosis. Importantly, EBV is known to be associated with many cancers, such as nasopharyngeal carcinoma (NPC), Burkitt's lym...

Claims

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Application Information

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IPC IPC(8): C07K19/00A61K39/12A61P31/22
CPCA61K2039/572A61K2039/70C12N2710/16222C12N2710/16122C07K2319/00C07K2319/40C07K2319/21C12N2710/16234C07K14/005A61K2039/6031C12N2710/16134A61P31/22A61P37/04C12N5/0638A61K39/245C12N7/00C12N2501/998
Inventor R·康纳D·维贾延德拉
Owner COUNCIL OF THE QUEENSLAND INST OF MEDICAL RES
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