Use of recombinant IgA1 isotype mAbs to prevent and antagonize transplacental transmission of flaviviruses in pregnant women

Background:

The field of flavivirus therapeutics, particularly for diseases like dengue, is of critical global importance due to the widespread prevalence and significant morbidity and mortality associated with these infections. Dengue alone threatens nearly 40% of the world’s population, causing hundreds of millions of infections each year. Despite this immense burden, effective prevention and treatment options remain limited. The absence of broadly effective vaccines, especially for individuals without prior exposure, and the lack of approved monoclonal antibody therapies highlight a pressing need for innovative solutions. Rapid, scalable, and easily deployable interventions are especially crucial during outbreaks, when traditional manufacturing and distribution methods for biologics can be too slow or resource-intensive to meet urgent demand. Current approaches to monoclonal antibody therapy for flaviviruses face several significant challenges. Conventional antibodies are complex molecules composed of separate heavy and light chains, requiring intricate and costly manufacturing processes, as well as specialized equipment for administration, such as intravenous infusions. These logistical hurdles hinder timely deployment, particularly in resource-limited settings or during sudden outbreaks. Furthermore, the predominant use of the IgG isotype in antibody therapies introduces a major safety concern: Antibody Dependent Enhancement (ADE), where antibodies can paradoxically worsen infection in partially immune individuals. This phenomenon has stymied the development of safe and effective antibody-based interventions for dengue, as IgG antibodies can facilitate viral entry into host cells and exacerbate disease severity. As a result, there is a critical unmet need for antibody-based therapies that are both safe from ADE and compatible with rapid, cost-effective, and scalable delivery platforms.

Technology Overview:

This technology is a single-chain recombinant IgA1 monoclonal antibody specifically engineered for the treatment and prevention of flavivirus infections, with a primary focus on dengue virus. The construct is designed as a single polypeptide that fuses the heavy and light chain variable regions via a GS3 linker, and incorporates an optimized leader sequence for efficient secretion, a human IgG1 hinge region for flexibility, and the Ca2 and Ca3 domains of the human IgA1 Fc region. This configuration enables the antibody to be delivered through nucleic acid vectors, such as DNA or RNA, allowing the patient’s own cells to produce the therapeutic antibody in vivo. The IgA1 isotype is chosen for its ability to neutralize all four dengue virus serotypes while avoiding Antibody Dependent Enhancement (ADE), a significant safety concern associated with IgG antibodies in dengue therapy. What differentiates this technology is its innovative single-chain design, which overcomes the complexity and inefficiency of delivering separate heavy and light chain genes typically required for monoclonal antibody therapies. By utilizing the IgA1 isotype and a streamlined genetic construct, the solution not only mitigates the risk of ADE but also enables rapid, scalable, and cost-effective production and deployment through nucleic acid delivery platforms. This approach eliminates the need for traditional antibody manufacturing and infusion infrastructure, making it especially valuable for rapid response during outbreaks and in resource-limited settings. Its specific applicability to expecting mothers addresses a unique and vulnerable population.

Advantages:

•    Enables in vivo production of therapeutic antibodies via nucleic acid delivery, reducing manufacturing complexity and cost.
•    Neutralizes all four dengue virus serotypes effectively, providing broad protection.
•    IgA1 isotype avoids Antibody Dependent Enhancement (ADE), enhancing safety compared to IgG antibodies.
•    Single-chain design fuses heavy and light chain variable regions, simplifying gene delivery and expression.
•    Rapid and scalable deployment potential for outbreak response without need for specialized infusion equipment.
•    Versatile applications including prophylaxis for travelers, military personnel, endemic populations, and outbreak containment.
•    Optimized molecular design ensures efficient secretion, flexibility, and preserved antibody effector functions.

Applications:

•    Prophylactic treatment for travelers
•    Outbreak containment in endemic regions
•    Rapid deployment for military personnel
•    Immediate post-exposure prophylaxis

Intellectual Property Summary:

Know-how based

Stage of Development:

TRL 2

Licensing Status:

This technology is available for licensing.