Monoclonal antibodies for the conserved feature of the coronavirus spike protein

The invention describes monoclonal antibodies targeting conserved epitopes on the S2 domain of coronavirus spike proteins, potentially useful for preventing or treating infections by inhibiting viral entry. These antibodies could aid in therapeutic formulations against coronaviruses like SARS-CoV-2, SARS-CoV, and MERS-CoV.

Background

The emergence of highly pathogenic coronaviruses, such as SARS-CoV-2, SARS-CoV, and MERS-CoV, has highlighted the urgent need for effective therapeutic and preventive measures. These viruses utilize the spike protein to mediate entry into host cells, with the S1 domain facilitating receptor binding and the S2 domain driving membrane fusion.

While most antibody therapies target the variable S1 domain, the conserved nature of the S2 domain across coronaviruses presents an attractive target for cross-reactive antibodies. However, the development of such antibodies is challenged by the conformational dynamics of the S2 domain during the fusion process, which complicates the identification of neutralizing epitopes.

Existing approaches primarily focus on the S1 domain due to its immunodominance and the ease of generating neutralizing antibodies against it. Yet, these antibodies often lack cross-reactivity and are susceptible to viral escape mutations. Consequently, there is a significant need for strategies that can elicit antibodies targeting conserved regions of the S2 domain, which could provide broad protection against current and future coronavirus outbreaks.

Technology description

The technology involves the creation of monoclonal antibodies that target conserved epitopes on the S2 domain of the spike protein of coronaviruses such as SARS-CoV, SARS-CoV-2, and MERS-CoV. These antibodies, identified through phage display technology, include 3A3, 4A5, and 4H2, and have been characterized for their binding affinities and specificities. The 3A3 antibody binds a conformational epitope on the S2 domain, crucial for viral fusion with host cells. This binding can inhibit the conformational changes necessary for viral entry, thus neutralizing the virus.

The technology also includes engineered proteins that mimic the spike protein's ectodomain, aiding in the study and development of these antibodies, which have potential therapeutic applications in preventing or treating coronavirus infections.

This technology is differentiated by its focus on the S2 domain of the spike protein, which is more conserved across coronavirus strains compared to other regions. This conservation means the S2 domain is less prone to mutations, making it a stable target for therapeutic interventions. The antibodies developed, particularly 3A3, target a conformational epitope that is accessible only when the spike protein is in a specific state, offering a novel mechanism of viral neutralization.

This approach contrasts with most antibodies that target the S1 domain, which is more variable and thus more susceptible to viral mutations. The technology's ability to target a conserved region potentially offers a broader and more durable defense against multiple coronavirus strains.

Benefits

Monoclonal antibodies target highly conserved epitopes on the S2 domain of coronavirus spike proteins.
Antibodies like 3A3 can inhibit viral fusion with host cells by binding to a conserved region, potentially neutralizing the virus.
The S2 domain is less prone to mutation, making it a stable target for therapeutic formulations to prevent or treat coronavirus infections.
Engineered proteins mimic the spike protein's ectodomain, aiding in the study and development of these antibodies.
Potential applications in therapeutic formulations to prevent or treat coronavirus infections by targeting the conserved S2 domain.
Antibodies can be used in cross-reactive detection reagents and as a tool for understanding viral mechanisms.
Humanized and affinity-matured versions of these antibodies can enhance therapeutic potential and reduce immunogenicity.
These antibodies can be incorporated into pharmaceutical formulations or used in diagnostic methods to detect coronavirus infections.