Gene therapy is a therapeutic strategy that has been wielded in a variety of diseases. It generally involves transferring genes via a vector into target cells, followed by gene addition, correction, or suppression, to provide or repair a missing or defective gene related to diseases. There are 3 facets of gene therapy:
The goal of gene therapy is to ensure the specificity of gene delivery to target cells and tissues and stable expression of therapeutic genes, and meanwhile, not disrupt the functional integrity of the cells. Therefore, gene therapy drugs are comprised of a therapeutic gene determining the specific therapeutic action, and a gene transfer vector, which contributes to the stability of delivery and expression of therapeutic genes.
Bispecific antibodies (BsAbs) can be associated with gene therapy in two ways.
With the flexibility in design and ability to simultaneously bind to both viral surface protein and molecules on the cell surface, BsAbs can act as adapter molecules to link the vector to a specific marker expressed on the target cell. Using BsAbs as adapters does not require modifications to the virus structure, thus avoiding possible damage to vector assembly, activity, and stability. Another remarkable advantage is that once an adapter for a particular vector has been proven effective, any other therapeutic gene can be delivered by the corresponding derivative of this vector.
On the other hand, BsAbs can be delivered to patients as therapeutic genes by gene therapy. Compared to being injected as proteins, local expression of BsAbs by gene therapy might contribute to achieving continuous and/or effective antibody concentration and/or better antibody biodistribution, and overcoming antibody clearance or difficulties in accessing tumors.
Fig.1 BsAbs and gene therapy.1
| Paper Title | Gene therapy with B-cell maturation antigen/CD3 bispecific antibody encoding plasmid DNA for treating multiple myeloma |
| Journal | British Journal of Haematology |
| Published | 2023 |
| Abstract | The efficacy of this strategy was assessed in this study. In comparison to the control-treated group, there was a significant tumor growth delay observed in mice treated with a single electroporation-enhanced intramuscular injection of BCMA/CD3 BsAb encoding plasmid DNA. In the following treatment, it was confirmed that the therapy had limited toxicity and did not result in any visible damage to the liver and kidney. These results jointly indicate that the gene therapy-based approach with BCMA/CD3 BsAb is both effective and safe and can be considered as a promising alternative for multiple myeloma (MM) treatment. |
| Result | Firstly, the study confirmed that BCMA/CD3 BsAbs promoted potent lysis of RPMI-8226 cells co-cultured with hPBMCs. The parameters of electroporation were also optimized. In a mouse xenograft model implanted with RPMI-8226 cells and reconstituted with hPBMCs, an in vivo efficacy analysis was conducted. The tumor growth was significantly suppressed by BCMA/CD3 BsAb and pCAG-BCMA/ CD3 gene therapy, which was also confirmed by positron emission tomography/computed tomography images, while the body weight was not affected in both treatments. It was also demonstrated that gene therapy with BsAb slightly increased the percentage of CD45+ tumor-infiltrating leucocytes. Additionally, both pCAG-BCMA/ CD3 and BCMA/CD3 BsAb boost the percentage of T cells in all CD45+ cells, compared to that in the control group. Moreover, confirmed by FCM and immunohistochemistry staining, the gene therapy and BsAb led to moderately improved serum interferon γ levels. |
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Fig.2 Anti-tumor activity of BCMA/CD3 BsAb gene therapy.2 |
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References
1. Nettelbeck, Dirk M. "Bispecific Antibodies and Gene Therapy." Bispecific Antibodies (2011): 327-347.
2. Peng, Fengping, et al. "Gene therapy with B-cell maturation antigen/CD3 bispecific antibody encoding plasmid DNA for treating multiple myeloma." British Journal of Haematology (2023).
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