Adenovirus (Ad) has been widely used both in experiment as a tool and in gene therapy development as a therapeutic gene delivery vehicle. More recently, it is shown that adenovirus has several traits that facilitate the design of oncolytic or tumor-selective recombinants. To be successfully engineered as a virus vector for wider oncolytic virotherapy applications, there are still obstacles to be overcome, such as hampered efficacy caused by neutralizing immunity, low tumor-targeting due to the lack of highly selective target and suitable targeting strategies. Therefore, novel strategies are needed for oncolytic adenovirus design and engineering. With years of experience in immunology and oncology, Creative Biolabs has established a comprehensive platform called OncoVirapy™ for oncolytic virus development services. By virtue of OncoVirapy™, we are able to generate the most efficacious adenovirus-based oncolytic viral vector.
Adenoviruses are non-enveloped viruses containing a linear double-stranded DNA genome within an icosahedral capsid. Among 57 human Ad serotypes, Ad serotype 5 (Ad5) has been the most commonly used for experimental and clinical purposes. It is clear that a variety of consideration has to be addressed including high levels of pre-existing humoral immunity when designing oncolytic adenovirus (OAd) vector for immune evasion and proper immune modulation for successful cancer immunotherapy
In general, to develop an OAd vector, three major aspects of engineering have to be taken into consideration, which are tumor selectivity, oncolytic efficacy and tumor infectivity.
Reference Oncolytic Virus
Currently, the most representative oncolytic adenovirus is Oncorine, the first approved oncolytic virus agent in the world for the treatment of nasopharyngeal cancer.
Oncorine (H101) is a recombinant oncolytic adenovirus developed by Shanghai Sunway Biotech in China, which is constructed by deleting E1B-55KD and E3 region of wild adenovirus type 5. Adenovirus E1B protein is necessary for the prevention of apoptosis of the infected host cells. By E1B deletion, Oncorine is unable to replicate in normal cells but can replicate in cancer cells due to P53 deficiency in cancer cells. Meanwhile, the deletion of E3 (a gene responsible for driving host cell apoptosis) enables engineered Oncorine to replicate in quantities to be more efficient in the destruction of cancers. The approval of Oncorine provides new promising alternative for nasopharyngeal cancer therapy and also promotes the research and development of oncolytic virotherapy.
E1A is the first viral gene expressed from the virus genome, differential splicing produces a shorter E1A-12S and a larger E1A-13S protein with several conserved regions. It was found that CR1 and CR2 mediate binding to pRB family proteins dissociating them from the E2F transcription factor. And when cycling cell or tumor cells are infected with adenovirus, the CR2 of E1A becomes dispensable. So oncolytic adenovirus with 24bp deletion in CR2 is able to replicate in tumor cells with Rb gene mutations for tumor cell growth is not solely dependent on Rb protein. E1b-19K is a homolog of Bcl2 that blocks apoptosis in infected cells, so E1b-19k mutants can induce not only proapoptotic cell death but also greater inflammatory response against tumor and thus may affect the oncolytic efficacy. Besides, deletion of E1b-55k is proposed to render adenovirus a tumor-selective virus for p53-defective tumors.
In addition to structural gene deletion, tumor selectivity of adenovirus can also be acquired by insertion of tumor-selective promoter. As E1A is the first protein expressed on infection and control the expression of others, replacing the promoter by a tumor-selective or tissue-selective promoter is a main strategy for tumor-specific OAd design.
Recently, inserting exogenous transgene has been an effective strategy for increasing the efficacy of oncolytic adenovirus. When arming OAd with transgene, one aim is to increase viral cytotoxicity by using prodrug-activating gene, toxins or immunostimulatory genes. To enhance virus replication, OAd can also be armed with genes that increase viral replication or progeny release. Another arming strategy is to engineer the virus encoding antibody, which has been widely used in cancer treatment. It is able to develop more potent oncolytic virus by combining the tumor-targeting and anti-tumor activity of therapeutic antibody with tumor lytic capacity of oncolytic virus. One similar conceptual strategy as arming with antibody is engineering OAd with bi-specific antibody for activation of endogenous T cells to kill tumor cells.
Hexon, fibers, penton and protein IX are four major determinants of the pharmacokinetics, biodistribution and cellular tropism of the virus. To achieve the maximum delivery of oncolytic adenovirus particle to tumor site, several obstacles have to be overcome, such as avoiding neutralizing antibodies and being captured by macrophages, inducing extravasation and penetration in tumors, etc. All these challenges can be approached with capsid modification.
With the increasing experience and knowledge of Ad system, coupled with the OncoVirapy™ platform, Creative Biolabs commits to developing efficacious oncolytic adenovirus for customer and enabling wider applications of adenovirus in oncolytic virotherapy of cancers. We also provide proof-of-concept validation study for oncolytic virus. Please feel free to contact us for more information and quotation.
Please feel free to contact us for a quote and further discussion with our scientists.
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