Neuraminidase – An Underestimated Target in Influenza Control
Most current influenza vaccines and antiviral drugs target two surface proteins – hemagglutinin (HA) and neuraminidase (NA). HA facilitates viral entry into cells, while NA is required for the release of new virions. Vaccines primarily induce antibodies against the HA head, which mutates frequently and necessitates seasonal vaccine updates due to antigenic drift.
Antibodies against the more stable HA stem region can offer broader protection, particularly against influenza A viruses, but they are primarily ineffective against influenza B. Meanwhile, neuraminidase mutates more slowly and is structurally conserved across influenza A subtypes and both B lineages, making it a promising target for new vaccines and drugs.
Currently, three neuraminidase inhibitors (NAIs) are used to treat influenza: zanamivir (ZAN), oseltamivir (OST), and peramivir. ZAN is highly effective against influenza A and B but has poor oral bioavailability and is rapidly cleared when administered intravenously. It is thus delivered via inhalation, which poses risks of bronchospasm in ventilated, asthmatic, or COPD patients. OST can be taken orally but is less potent, especially against influenza B, and resistance develops more readily.
To enhance the best-in-class activity of ZAN and improve its pharmacokinetics, U.S. researchers developed CD388 – two ZAN molecules fused to an Fc domain of human IgG1. This construct allows prolonged circulation and enhanced neuraminidase binding. CD388 interacts with multiple NA sites on a single virion or between virions, promoting aggregation and preventing viral entry into host cells.
CD388 Inhibits Diverse Influenza Strains In Vitro
CD388 effectively inhibited the neuraminidase activity of various influenza A and B strains at very low concentrations. It retained potency against H1N1, H3N2, and influenza B viruses, including highly pathogenic avian strains H5N1 and H7N9. In contrast, oseltamivir and zanamivir lost efficacy against the H7N9 strain A/Shanghai/01/2013.
CD388 outperformed ZAN and OST in antiviral potency, especially against avian influenza, attributed to its dual mechanism – NA inhibition and virion aggregation. CD388 showed comparable activity to baloxavir against most influenza strains but was slightly less potent against some avian HPAI strains. In cell models, CD388 showed high selectivity and no toxicity, indicating superior safety and versatility compared to other NAIs.
CD388 Effectively Treats Severe Influenza in Mice
A single 0.3 mg/kg intramuscular dose of CD388 protected mice from lethal H1N1 infection when administered two hours post-infection. Mice experienced only minor, transient weight loss. CD388 reduced lung viral load and inflammatory cytokines IL-6 and MCP-1 in a dose-dependent manner.
In contrast, oseltamivir failed to protect at standard doses and required a 10-fold increase to achieve 80% survival. OST treatment caused significant weight loss and had modest antiviral effects, though it also reduced IL-6 and MCP-1 levels in the lungs.
CD388 maintained efficacy against other influenza A (H1N1, H3N2) and B (Victoria, Yamagata) strains. Single doses ranging from 0.3 to 1 mg/kg provided complete protection with minimal side effects.
In immunodeficient mice – a model for elderly and immunocompromised patients – CD388 was also effective against H1N1 at a single 1 mg/kg dose. Oseltamivir and baloxavir were either ineffective or only partially protective in this model.
These findings support CD388 as a potent and durable therapeutic option even for high-risk groups.
CD388 Provides Long-Term Prophylaxis Against Influenza
CD388 can offer long-lasting protection following a single dose. Its half-life was 106 hours in mice and 364 hours in macaques, due to Fc modifications enhancing FcRn receptor binding and extending circulation.
CD388 remains stable in vivo. After administration, it persists in its original form and is distributed evenly across body fluids. Its blood concentration remains around 34% of its plasma level.
In mice, a single 1 mg/kg dose administered seven days before infection achieved protective serum levels (~1 µg/mL) and prevented disease. CD388 protected against multiple influenza A and B strains, including H1N1, H3N2, Victoria, and Yamagata.
The low serum threshold for protection, long-acting profile, and pharmaceutical stability highlight CD388’s potential as a universal preventive against seasonal and pandemic influenza.
CD388 Is Effective Against NAI-Resistant Influenza Strains
CD388 retained efficacy against viruses with NA mutations that reduce sensitivity to oseltamivir and zanamivir. In mouse models of lethal infection, it protected 0.3 mg/kg for both NAI-sensitive and NAI-resistant strains. In contrast, OST and ZAN required much higher doses or lost effectiveness.
CD388 Does Not Induce Drug Resistance
In repeated serial passage experiments in cell cultures infected with influenza A and B, CD388 caused only minimal resistance development after 10 cycles. Mutations near the CD388 binding site were rare. Even when present, CD388 retained over two-thirds of its potency and remained equal or superior to other NAIs. The required effective concentration remained unchanged across resistant and sensitive strains, indicating a low likelihood of resistance emergence.
Conclusion
Seasonal influenza remains a significant health threat, especially with the emergence of new strains like H5N1. Low vaccine uptake, limited efficacy (10–60% depending on the season), and poor immune responses in older people and immunocompromised leave many vulnerable.
CD388 combines zanamivir’s potency with the extended activity of monoclonal antibodies. It is effective against a broad spectrum of influenza A and B strains, including NAI-resistant variants, and remains potent in immunocompromised settings. Its small size and polyvalent structure support efficient lung penetration, sustained viral suppression, and preventive efficacy.
CD388 is currently undergoing phase 2b clinical trials as a universal influenza prophylactic for the 2024–2025 season.
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Reference
Drug-Fc conjugate CD388 targets influenza virus neuraminidase and is broadly protective in mice
