Pathogenicity Manipulation (Attenuation)

With years of exploration in oncolytic virus development, Creative Biolabs has built an advanced oncolytic virus engineering platform, which enables to manipulate the pathogenicity of oncolytic virus to meet customers' research, preclinical study and drug development.

Nowadays, oncolytic virus therapy has become a potential new therapeutic approach for cancer treatment. Oncolytic virus refers to a genetically engineered or naturally occurring virus which enables to selectively replicate in and kill cancer cells without damaging the normal tissues. Different from common gene therapy where a virus is used as a mere carrier for transgene delivery, oncolytic virus therapy utilizes the virus itself as an active drug reagent. However, oncolytic viruses usually have a strong pathogenicity and they may cause damage in humans. Thus, under the progress of modern techniques of genetic engineering and enhancing knowledge regarding the functions and structures of viral genes, designing and manipulating the viral genome to generate a non-pathogenic virus has become the standard approach for oncolytic virus development. To achieve this goal, pathogenic elements of oncolytic virus should be mutated or deleted.

Scientists from Creative Biolabs provide a full range of pathogenicity manipulation methods for oncolytic virus development. We provide our clients with customized solutions according to the needs of your project requirements. Following are several generally strategies.

Adenoviruses with Deletions in E1b Gene

The pathogenicity of adenoviruses is usually manipulated by E1b Gene Deletions. Adenoviruses (Ads) are most widely applied for oncolytic virotherapy, on account of their infection efficacy, safety, easy genetic modification, as well as high titer production features. Ads with deletion of E1b55K have showed great ability in destroy cancer cells. Oncolytic adenovirus H101, one of the E1b55K-deleted Ads, has been applied for the treatment of late-stage cancers and it is the first approved virotherapy agent.

Fig 1. Schematic diagram of engineered replication selectivity of oncolytic adenoviruses by deletion of the E1A, E1B 19K or E1B 55K gene. (Wong, H. H., 2010)

HSV-1 with Deletions in the γ34.5 and α47 Genes

Take the T-VEC as an example, which is a double-mutated HSV-1 with deletions in the γ34.5 and α47 genes. Besides, the human granulocyte-macrophage colony-stimulating factor (GM-CSF) gene is inserted into the deleted γ34.5 loci. The deletion in the γ34.5 genes plays an important role in attenuation of pathogenicity and cancer-selective replication. Because the γ34.5 gene works to negate the host cell's shut-off of protein synthesis upon viral infection, inactivation of c34.5 makes the virus unable to replicate in normal cells.

Vaccinia Virus with Mutation in the TK Gene

The pathogenicity of vaccinia virus usually enables to be manipulated by TK gene mutation. For example, a genetically engineered vaccinia virus, JX-594, has a mutation in the TK gene, making cancer cell-selective replication, and an insertion of the human GM-CSF gene, enhancing the antitumor immune response. Besides, JX-594 has a LacZ gene insertion as a marker. There are a variety of advantages of using vaccinia virus, such as strong cytotoxicity, intravenous stability for delivery, and extensive safety experience as a live vaccine.

Fig 2. General oncogenic mutations in cancer cells encourage replication of the genetically engineered oncolytic JX-594 virus1. (Galanis, E. 2011)

Other Services on Oncolytic Virus Engineering Platform

• Immunogenicity Manipulation
• Antibody-expressing Oncolytic Virus
• Cytokine/Chemokine-expressing Oncolytic Virus
• Immune Checkpoint Inhibitor-expressing Oncolytic Virus

With our well-established oncolytic virus engineering platform, the experienced scientists at Creative Biolabs are dedicated to helping you develop unique oncolytic virus. We also provide other various services regarding oncolytic virus development. Please feel free to contact us for more information and a detailed quote.

Reference:

1. Wong, H. H., (2010). "Oncolytic viruses for cancer therapy: overcoming the obstacles." Viruses, 2(1), 78-106.
2. Galanis, E. (2011). "Cancer: Tumour-fighting virus homes in." Nature, 477(7362), 40-41.
3. Fukuhara, H., (2016). "Oncolytic virus therapy: A new era of cancer treatment at dawn." Cancer science.

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