Characterization of a novel humanized heavy chain antibody targeting endogenous retroviruses with anti-lymphoma activity

Spriano, F.; Cascione, L.; Sgrignani, J.; Bendik, N.; Napoli, S.; Sartori, G.; Cannas, E.; Gong, T.; Arribas, A. J.; Pizzi, M.; Rossi, D.; Robbiani, D. F.; Cavalli, A.; Bertoni, F.

doi:10.1101/2024.01.17.576027

bioRxiv · 10.1101/2024.01.17.576027

Characterization of a novel humanized heavy chain antibody targeting endogenous retroviruses with anti-lymphoma activity

Spriano, F.·Cascione, L.·Sgrignani, J.·Bendik, N.·Napoli, S.·Sartori, G.·Cannas, E.·Gong, T.·Arribas, A. J.·Pizzi, M.·Rossi, D.·Robbiani, D. F.·Cavalli, A.·Bertoni, F.

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Abstract

Lymphomas continue to pose therapeutic challenges, with a considerable portion of patients facing refractory disease. This study focuses on Diffuse Large B-cell Lymphoma (DLBCL), the most prevalent lymphoma type. Within the human genome, transposable elements (TEs), particularly Human Endogenous Retroviruses (HERVs), constitute a significant yet understudied portion. Among HERVs, the HERV-K family, specifically HERV-K113 and HERV-K115, has intact open reading frames. Epigenetic regulation tightly controls HERV expression, and aberrant expression has been observed in various cancers, including lymphomas. This research investigates the potential of HERV-K as a therapeutic target in DLBCL. The study encompasses comprehensive methods, including RNA extraction, PCR detection, flow cytometry, immunoblotting, peptide prediction, phage display, surface plasmon resonance, ELISA, antibody-dependent cell-mediated cytotoxicity, internalization assays, and bioinformatic analysis. Results reveal the presence and expression of HERVs in lymphoma patients and cell lines, with the HERV-K envelope protein identified as a crucial contributor to lymphoma cell growth. Moreover, the study identifies immunogenic regions of HERV-K, leading to the development of a humanized camelid nanobody (FF-01) with potential therapeutic applications. Furthermore, bioinformatic analysis differentiates DLBCL subgroups based on TE expression, providing insights into prognostic variations. Patients with high HERV-K113 expression show activation of pathways related to antiviral responses, suggesting a viral mimicry state. In conclusion, the study highlights the clinical relevance of HERVs in lymphomas, proposing them as novel therapeutic targets. The newly developed nanobody FF-01 demonstrates anti-lymphoma activity through antibody-dependent cellular cytotoxicity and internalization. This research opens avenues for exploring endogenous retroviruses as targets for immunotherapy in lymphomas, showcasing the potential of FF-01 as a promising candidate for further investigation.

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Spriano, F., Cascione, L., Sgrignani, J., Bendik, N., Napoli, S., Sartori, G., Cannas, E., Gong, T., Arribas, A. J., Pizzi, M., Rossi, D., Robbiani, D. F., Cavalli, A., Bertoni, F.. 2024-01-18. Characterization of a novel humanized heavy chain antibody targeting endogenous retroviruses with anti-lymphoma activity. https://doi.org/10.1101/2024.01.17.576027

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