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Compositions and methods for treatment of cytomegalovirus

A composition and retrovirus technology, applied in the field of composition for treating cytomegalovirus, can solve problems such as toxicity and limited curative effect

Pending Publication Date: 2018-04-06
VARIATION BIOTECHNOLOGIES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, existing therapies are characterized by significant toxicity and limited efficacy, especially for late-onset disease (Boeckh M., 2004 Pediatr Transplant 8 (Suppl. 5): 19-27; Limaye AP., 2004 Transplantation 78(9 ):1390-6), and they have no effect on congenital HCMV disease

Method used

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  • Compositions and methods for treatment of cytomegalovirus
  • Compositions and methods for treatment of cytomegalovirus
  • Compositions and methods for treatment of cytomegalovirus

Examples

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Embodiment 1

[0208] Embodiment 1: Construction of DNA expression plasmid

[0209] This example describes the development of expression plasmids and constructs for expression of recombinant HCMV gene sequences such as gB, gB-G, gH-G and Gag / pp65 fusion gene sequences. A standard expression plasmid usually consists of the following: mammalian-derived promoter sequence, intron sequence, polyadenylation signal sequence (PolyA), pUC origin of replication sequence (pUC-pBR322 is the colE1 origin of replication origin / site and antibiotic resistance genes for replication of plasmids in bacteria such as E. coli (DH5α) and as selectable markers for plasmid plaque selection. Following the introns in the plasmid are multiple restriction enzyme sites that can be used for splicing into a gene or partial gene sequence of interest.

[0210] Propol II expression plasmid contains pHCMV (for early promoter of HCMV), β-globin intron (BGL intron), rabbit globulin polyadenylation signal sequence (PolyA), pUC o...

Embodiment 2

[0213] Embodiment 2: the production of virus-like particle (VLP)

[0214] This example describes methods for producing virus-like particles (VLPs) containing various recombinant HCMV antigens described in Example 1.

[0215] HEK 293T cells (ATCC, CRL-11268) were transiently transfected with MMLV-Gag DNA expression plasmids using the calcium phosphate method and co-transfected with gB or gB-G (data not shown) or gH-G DNA expression plasmids. Alternatively, cells were transfected with Gag / pp65 DNA expression plasmids and co-transfected with gB or gB-G (data not shown) or gH-G DNA expression plasmids. It will be appreciated that cells can be transfected with MMLV-Gag DNA expression plasmids and co-transfected with gB and gH-G or both gB-G and gH-G DNA expression plasmids. Multiple HCMV antigens expressed by HEK293 cells were confirmed by flow cytometry ( figure 2 A). 48 to 72 hours after transfection, the VLP-containing supernatant was harvested and filtered through a 0.45 μm...

Embodiment 3

[0216] Example 3: Physicochemical Characterization of Virus-Like Particles (VLPs)

[0217] Physicochemical analysis of VLPs included particle size determination and evaluation of polydispersity index using a Malvern Instrument Zeta-Sizer Nanoseries (ZEN3600). Exemplary results obtained from nanonization analysis are in Figure 3A and 3B shown in . An exemplary VLP composition (gH-G / pp65 bivalent VLP composition) was produced in two different laboratories using the same recombinant expression vector and both VLP preparations gave average particle sizes ranging from 150 nm to 180 nm in diameter . This is consistent with the size of CMV virions, which are reported to be in the range of 150 nm to 200 nm (1997 J Pathol 182:273-281 ). A low polydispersity index (PdI) of 0.214 to 0.240 indicates product homogeneity and narrow size distribution.

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Abstract

The present disclosure provides compositions and methods useful for treating HCMV infection. As described herein, the compositions and methods are based on development of immunogenic compositions thatinclude virus-like particles (VLPs) which comprise one or more Moloney Murine leukemia virus (MMLV) core proteins and include one or more HCMV epitopes, such as, for example, from HCMV envelope glycoproteins gB and / or gH and / or tegument protein pp65. Among other things, the present invention encompasses the recognition that a combination of antigens (e.g., envelope glycoproteins and structural proteins) can lead to beneficial immune responses, for example that include both a humoral response (e.g., production of neutralizing antibodies) and a cellular response (e.g., T-cell activation).

Description

[0001] This application is a divisional application of a Chinese patent application with application number 201280066355.X. The original application is the PCT international application PCT / IB2012 / 002854 filed on November 9, 2012, which entered the Chinese national phase on July 4, 2014 . [0002] Cross References to Related Applications [0003] This application claims priority to U.S. Provisional Application No. 61 / 558,800, filed November 11, 2011, and U.S. Provisional Application No. 61 / 654,157, filed June 1, 2012, the contents of which are hereby incorporated by reference in their entirety . technical field [0004] The present invention relates to compositions and methods for treating cytomegalovirus. Background technique [0005] Human cytomegalovirus (HCMV) (beta-herpesvirus) is a ubiquitous pathogen. HCMV infection is usually overlooked in immunocompetent persons, with the mildest and nonspecific symptoms. In contrast, certain high-risk groups, such as in immunos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/245A61K39/295C12N15/63A61P31/22A61P37/04C07K14/045C07K14/145C07K19/00C12N15/38C12N15/48C12N15/86C12N7/01C12N7/04
CPCA61K39/245C07K14/005A61K2039/5258A61K2039/70C07K2319/03C07K2319/00C12N2710/16134C12N2760/20234C12N2740/13023A61P31/22A61K39/12C12N2760/20245A61P31/20
Inventor 大卫·E·安德森安妮-凯瑟琳·弗卢基格
Owner VARIATION BIOTECHNOLOGIES INC
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