Multispecific antibodies against infectious diseases
Antibody therapy is safe and effective against infectious diseases. It is complementary to vaccines and mostly needed by people that cannot or do not want to be vaccinated, cannot mount an adequate response (e.g. immunosuppressed) or have waning protection over time. Antibodies can be used therapeutically after symptoms appear, being immediately effective, or they can protect prophylactically pre- or post-exposure.
SARS-CoV-2 has shown both the power of antibodies, which were approved even before vaccines and have been a life saver for many, and their weakness, because early adoption was lacking and because all approved antibodies were rendered ineffective by emerging variants. Research to overcome these limitations is warranted.
Resistance to viral mutations can be achieved by targeting highly conserved, potently neutralizing regions that are critical for viral function and thus not easily altered by the pathogen, such as the fusion peptide. However, fusion peptides are usually inaccessible on the viral surface and exposed only through structural rearrangements during the molecular infection process.
Here we aim to design novel, multispecific antibodies capable of reaching potently neutralizing, conserved, but normally inaccessible epitopes. The idea is to anchor one half of a bispecific antibody to conserved, accessible but not neutralizing epitopes. The other half targets the fusion peptide or similar. It remains free on the viral surface outside the cells, but it is ideally located to immediately bind the fusion peptide when it is exposed after cleavage or endocytosis.
We will engineer and extensively characterize such multispecific antibodies against the SARS-CoV-2 Spike, fully expecting to be able to neutralize viruses as distant as MERS. To prove the power and versatility of the approach, and for risk diversification, we will also design similar multispecifics against the flavivirus E-protein.
Adoption of antibody therapy is hampered by uncomfortable and logistically complicated administration routes, often intravenous; and cost, particularly relevant for middle- and low-income countries where infectious diseases often have larger impact. mRNA delivery, which received a huge boost from the SARS-CoV-2 vaccines success, has the potential to solve such problems. A simple jab of micrograms of mRNA can stimulate production of the equivalent of grams of antibodies in the patient. However, current mRNA technology does not allow delivery of multispecifics or antibody cocktails, which are required for the above approach and more generally to resist to and prevent formation of viral escape mutations. Simultaneous mRNA delivery of two or more antibodies has practical and regulatory hurdles.
A second goal of this proposal is to establish a robust mRNA system for delivery of novel bispecific antibody constructs engineered for optimal production through mRNA delivery, overcoming the chain shuffling and uncertain stoichiometry of currently available technology. We will verify their production yield, stability, biophysical and molecular properties, ability to neutralize the virus and protect from infection in-vitro and in-vivo. The characteristics of mRNA delivered antibodies will be compared to those of the same constructs produced with traditional methods.
This interdisciplinary project covers antibody and mRNA engineering, cellular and biophysical assays, immunotherapy, physiology and immunotherapy for infectious diseases. It has the potential for high impact scientific publications and excellent training opportunities for PhD students and Postdocs. We already have reagents, assays, expertise and international collaborations ensuring prompt and effective project progression.