Immunogenicity Manipulation Service
Introduction
Oncolytic virotherapy has been an emerging tumor treatment method in recent years. However, there are some caveats in the process of clinical use. For example, the anti-tumor effect of oncolytic viruses is limited by the immunogenicity of the virus, which may induce neutralizing antibodies to inactivate the virus and reduce the patient's viral load. Therefore, immunogenicity manipulation is required to prevent rapid viral clearance and ensure sustained viral activity at the tumor site. The necessity of immunogenicity manipulation is also reflected in enhancing the therapeutic effect and improving the safety of treatment.
Based on years of experience, Creative Biolabs has established a mature oncolytic virus engineering platform to edit genomes to reduce immunogenicity and improve drug safety in research and preclinical development, and to provide a full range of customized solutions for oncolytic virus research and development.
Modification of the Capsid
Adenovirus (Ad) is a class of oncolytic viruses, which rely on the Coxsackie and adenovirus receptor (CAR) on the cell surface to infect target cells. The low expression level of CAR on the surface of most tumor cells makes Ads unable to effectively play a role in oncolytic. The Ads capsid protein is the basis for virus attachment and internalization, and appropriate changes in its structure can improve the efficiency of Ad infection. The following table shows the commonly used applications of modifications to capsid protein structures:
| Capsid protein structure | Insertion site | Sequence | Advantage |
|---|---|---|---|
| Fiber | HI-loop or C-terminal | RGD-4C, pK7, antagonists sequence, detectable surface biotin, TRAIL, etc. |
Enhanced targeting, replication capacity, infection efficiency, and tumor suppression |
| Penton | Penton Base | ||
| Hexon | HVR5 | ||
| pⅨ | C-terminal | ||
| pⅢa | N-terminal |
The function of Ad can also be optimized by chimeric modification of the fibrin nodule proteins of different serotypes. For example, the fibrin of Ad7, Ad35, Ad40, and Ad41 is very different from that of Ad5, so the corresponding parts of the fibrin genes of these serotypes can be used to replace part or all of Ad5's fibrin genes to escape the body's immune response. To reduce immunogenicity.
Antibody Secretion
By enhancing the secretion of antibodies against auto immunogenic sites of the oncolytic virus, it can preempt the antigen sites that may trigger immune responses after the virus has entered the body, prevent the body's immune system from recognizing the oncolytic virus, reduce the production of neutralizing antibodies, and make the oncolytic virus can play an oncolytic role in the body for a longer time.
Cytokine/chemokine Expression
Enabling OV to express cytokines or chemokines can effectively recruit immune cells to virus-infected tumor cells and promote the oncolytic effect of OV. Researchers have combined NK cells for the better killing of neuroblastoma by constructing HSV expressing IL-211 or expressing IL-12-VACV2. In addition, GM-CSF, TNF-α, IL-2, IL-12, IL-15, IL-18, IL-21, IL-23, IFN-β, CCL5, CCL20 are also commonly used genes.
Load with Immune Checkpoint Inhibitors
Immune checkpoints expressed in immune cells can regulate the degree of immune activation and prevent the occurrence of autoimmune reactions. Tumor cells can use immune checkpoints to evade the surveillance of the immune system. Therefore, OV can be designed to target immune checkpoints, such as HSV3 or VACV expressing αPD-L1, to enhance anti-tumor activity and immune activation. The measles virus (MV) encoding αCTLA-44 is generated, and the anti-tumor proliferation activity was significantly enhanced.
Expression of pro-inflammatory factors
The insertion of proinflammatory cytokine-related genes in the viral genome can make the virus-infected cells express these cytokines, such as p53, PTEN, p16, Rb, TRAIL, and Smac, activate the immune system, attract the aggregation of immune cells, promote the proliferation and differentiation of immune cells, and then have an indirect killing effect on the surrounding tumor cells. In practical application, it is also necessary to ensure the safety and efficacy of the virus and how to avoid the autoimmune response caused by excessive activation of the immune system.
Other Services on Oncolytic Virus Engineering Platform
- Pathogenicity Manipulation (Attenuation)
- Antibody-expressing Oncolytic Virus
- Cytokine/Chemokine-expressing Oncolytic Virus
- Immune Checkpoint Inhibitor-expressing Oncolytic Virus
Based on our well-established OVs engineering platform, the experienced scientists here at Creative Biolabs are dedicated to helping you develop a unique oncolytic virus. Please feel free to contact us for more information and a detailed quote.
References
- Chu, Yaya, et al. "Combinatorial immunotherapy with anti-ROR1 CAR NK cells and an IL-21 secreting oncolytic virus against neuroblastoma." Molecular Therapy Oncology 33.1 (2025).
- Kurokawa, Cheyne, et al. "Mediation of antitumor activity by AZD4820 oncolytic vaccinia virus encoding IL-12." Molecular Therapy Oncology 32.1 (2024).
- Wang, Lei, et al. "Enhanced therapeutic efficacy for glioblastoma immunotherapy with an oncolytic herpes simplex virus armed with anti-PD-1 antibody and IL-12." Molecular Therapy Oncology 32.2 (2024).
- Engeland, Christine E., et al. "CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy." Molecular Therapy 22.11 (2014): 1949-1959.