CD388: A universally protective Drug-Fc Conjugate that targets influenza virus neuraminidase

Dohrmann, S.; Levin, J.; Cole, J. N.; Borchardt, A.; Amundson, K.; Almaguer, A.; Abelovski, E.; Grewal, R.; Zuill, D.; Dedeic, N.; Hough, G.; Fortier, J.; Donatelli, J.; Lam, T.; Chen, Z.-Y.; Jiang, W.; Haussener, T.; Noncovich, A.; Balkovec, J. M.; Bensen, D. C.; Ong, V.; Brady, T. P.; Locke, J.; Stein, J. L.; Tari, L. W.

doi:10.1101/2024.06.04.597465

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bioRxiv · 10.1101/2024.06.04.597465

CD388: A universally protective Drug-Fc Conjugate that targets influenza virus neuraminidase

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Abstract

The ability of the influenza virus to elude humoral immunity by rapid antigenic shift presents a sustained and urgent threat to human health. Globally, seasonal influenza causes an estimated 3 - 5 million cases of severe disease and 300,000 - 500,000 deaths annually, with increased potential for mortality during pandemics1. The recent outbreaks of avian H5N1 in bird populations, subsequent spread to cattle and appearance in humans, highlight the need for effective broad-spectrum influenza antivirals for treatment, prophylaxis and pandemic preparedness. The narrow, strain-specific immunity induced by current seasonal vaccines and mismatches between vaccine strains and circulating viruses result in limited vaccine effectiveness (VE) rates2. Furthermore, VE is even lower in immune-compromised and - senescent populations3. Strategies that provide durable, universal influenza protection in healthy and high-risk populations are urgently needed. Here, we describe CD388, a first-in-class antiviral drug-Fc conjugate (DFC) in clinical trials for seasonal influenza prevention (NCT05285137 and NCT05523089). CD388 comprises a multivalent small molecule inhibitor of influenza virus neuraminidase (NA) linked to a CH1-Fc hybrid domain of human IgG1 engineered for extended half-life. CD388 demonstrated potent, universal activity across influenza A and B viruses, including high pathogenicity and NA resistant strains, a low potential for resistance development, and efficacy in lethal mouse infection models. CD388 is the first therapeutic with the potential for universal prevention of influenza A and B in healthy and high-risk populations.

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Dohrmann, S., Levin, J., Cole, J. N., Borchardt, A., Amundson, K., Almaguer, A., Abelovski, E., Grewal, R., Zuill, D., Dedeic, N., Hough, G., Fortier, J., Donatelli, J., Lam, T., Chen, Z.-Y., Jiang, W., Haussener, T., Noncovich, A., Balkovec, J. M., Bensen, D. C., Ong, V., Brady, T. P., Locke, J., Stein, J. L., Tari, L. W.. 2024-06-04. CD388: A universally protective Drug-Fc Conjugate that targets influenza virus neuraminidase. https://doi.org/10.1101/2024.06.04.597465

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