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Updated: Apr 6, 2026
Murine Model of CD40-activation of B cells
Published on: March 5, 2010
2-fluoro-RNA oligonucleotide CD40 targeted aptamers for the control of B lymphoma and bone-marrow aplasia
Mario Martinez Soldevilla1, Helena Villanueva1, Maurizio Bendandi2
1CIMA, Program of Molecular Therapies, Aptamer Unit, Universidad de Navarra, Avenida Pio XII 55, 31008, Pamplona, Spain.
Abstract:
Recent studies have underscored the importance of immunomodulatory antibodies in the treatment of solid and hematological tumors. ODN-Aptamers are rising as a novel class of drugs that can rival therapeutic antibodies. The success of some of the current cancer immunotherapy approaches in oncological patients depends on the intrinsic antigenicity of each tumor as has recently been disclosed, and it is hampered in those patients that are treated with myeloablative chemotherapy or radiotherapy, which induce profound immunosuppression. CD40 agonist and antagonist molecules offer a new therapeutic alternative which has the potential to generate anticancer effects by different mechanisms. HS-SELEX was performed to identify high-affinity aptamers against CD40, and three therapeutic CD40 constructs were engineered as: CD40 agonist aptamer, CD40 antagonist aptamer and CD40 agonistic aptamer-shRNA chimera. It is shown that CD40 agonist aptamers can be used to promote bone-marrow aplasia recovery. CD40 antagonist aptamers are revealed to have a direct antitumor effect on CD40-expressing B-cell lymphoma in vitro and in vivo. Further, in order to identify a therapeutic reagent that will generate the optimal conditions for cancer immunotherapy (antigen-presenting cell activation, tumor antigenicity enhancement and bone-marrow aplasia recovery), CD40 agonist aptamer-shRNA chimera was generated to target the inhibition of the Nonsense mRNA Mediated Decay (NMD) to tumor cells.
Insights
Oligonucleotide-aptamers targeting CD40 show promise as cancer therapeutics. CD40 agonist aptamers aid bone marrow recovery, while antagonist aptamers target B-cell lymphoma, offering new avenues in cancer immunotherapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Immunomodulatory antibodies are crucial for treating various cancers.
- Oligonucleotide-aptamers (ODN-Aptamers) are emerging as potent alternatives to therapeutic antibodies.
- Cancer immunotherapy effectiveness is limited by tumor antigenicity and chemotherapy-induced immunosuppression.
Purpose of the Study:
- To engineer novel therapeutic constructs targeting CD40 for cancer treatment.
- To evaluate the potential of CD40-targeting aptamers in enhancing cancer immunotherapy.
Main Methods:
- High-throughput SELEX (Systematic Evolution of Ligands by Exponential Enrichment) was employed to identify high-affinity aptamers against CD40.
- Three distinct CD40 aptamer constructs were engineered: agonist, antagonist, and an agonist-aptamer-shRNA chimera.
Main Results:
- CD40 agonist aptamers demonstrated efficacy in promoting bone marrow aplasia recovery.
- CD40 antagonist aptamers exhibited direct anti-tumor effects against CD40-expressing B-cell lymphoma in vitro and in vivo.
- A CD40 agonist aptamer-shRNA chimera was developed to inhibit Nonsense-mediated mRNA Decay (NMD) in tumor cells, aiming to optimize conditions for cancer immunotherapy.
Conclusions:
- Engineered CD40 aptamers offer versatile therapeutic strategies for cancer treatment, including bone marrow recovery and direct tumor targeting.
- The CD40 agonist aptamer-shRNA chimera presents a novel approach to enhance cancer immunotherapy by modulating tumor cells and immune responses.
