Generation of a single-chain recombinant IgA1 isotype antibody compatible with in vivo nucleic acid delivery for the treatment and prevention of flavivirus infection

Background:

Flavivirus infections, including those caused by dengue and Zika viruses, represent a significant global health concern, affecting billions of people and resulting in hundreds of millions of infections annually. These diseases can lead to severe illness and death, particularly in regions where healthcare resources are limited and outbreaks are frequent. The lack of effective vaccines or therapeutics for many at-risk populations underscores the urgent need for new approaches to both prevent and treat these infections. Monoclonal antibody therapies have shown promise in neutralizing viral pathogens and providing immediate immunity, making them attractive candidates for outbreak response and prophylactic use in vulnerable populations. However, current monoclonal antibody therapies face several critical limitations that hinder their widespread deployment during flavivirus outbreaks. Traditional antibodies are complex molecules composed of two heavy and two light chains, requiring intricate and costly manufacturing processes in specialized facilities. These therapies are typically administered via intravenous infusion, necessitating trained personnel and advanced medical infrastructure, which are often unavailable in outbreak settings or resource-limited regions. Additionally, IgG-based antibodies carry the risk of Antibody Dependent Enhancement (ADE), a phenomenon that can worsen disease severity in individuals with partial immunity, further complicating their use for dengue and related viruses. Existing nucleic acid-based delivery systems are also challenged by the need to co-express multiple antibody chains, reducing efficiency and scalability for rapid response.

Technology Overview:

This technology is a single-chain recombinant IgA1 monoclonal antibody construct specifically engineered for nucleic acid-based delivery to combat flavivirus infections such as dengue and Zika virus. Unlike conventional monoclonal antibody therapies, which require complex manufacturing and infusion processes, this solution utilizes a single-chain format that fuses the heavy and light chain variable regions into one polypeptide, linked to a truncated IgA1 Fc region. This design allows the antibody to be encoded by a single DNA or RNA molecule, enabling direct in vivo expression after administration. The optimized construct incorporates an engineered leader sequence, a GS3 linker, a human IgG1 hinge, and the Ca2 and Ca3 domains of the human IgA1 Fc, ensuring efficient production and robust neutralizing activity against all four dengue virus serotypes. Importantly, the IgA1 isotype was chosen because it does not mediate Antibody Dependent Enhancement (ADE), a major safety concern in dengue treatment. What differentiates this technology is its novel single-chain IgA1 architecture, which is the first of its kind, as previous single-chain antibody constructs have focused on the IgG1 isotype. The strategic molecular design (combining variable regions, linker, and hinge domains) enables high-level expression and functional activity from a single nucleic acid vector, greatly simplifying manufacturing and deployment. Its compatibility with DNA or RNA delivery platforms means that the antibody can be rapidly and cost-effectively produced and administered, bypassing the need for traditional biomanufacturing and infusion infrastructure. This approach not only addresses the urgent need for safe and effective flavivirus therapeutics but also enables rapid outbreak response, making it suitable for use in travelers, military personnel, residents in endemic regions, and for targeted containment of transmission clusters.

Advantages:

•    Enables rapid, scalable, and cost-effective production and delivery of therapeutic antibodies via nucleic acid vectors (DNA/RNA).
•    Single-chain IgA1 antibody format simplifies manufacturing by encoding both heavy and light chain variable regions in a single polypeptide.
•    Provides broad neutralization against all four dengue virus serotypes, addressing a major global health challenge.
•    IgA1 isotype avoids Antibody Dependent Enhancement (ADE), improving safety compared to traditional IgG antibodies.
•    Facilitates immediate immunity for prophylactic and therapeutic use in diverse populations including travelers, military personnel, and residents in endemic areas.
•    Eliminates need for specialized infusion equipment, enabling easier and faster deployment during outbreaks.
•    Preserves unique IgA1 effector functions while optimizing expression and function through engineered molecular design.

Applications:

•    Dengue outbreak rapid response
•    Traveler prophylactic immunization
•    Military deployment disease prevention
•    Close contact post-exposure prophylaxis
•    Endemic region population protection

Intellectual Property Summary:

Know-how based

Stage of Development:

TRL 3

Licensing Status:

This technology is available for licensing.