IBT, Scripps Win $6.6M to Develop Pan-Ebolavirus Vaccine

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A collaboration between Integrated BioTherapeutics (IBT) and The Scripps Research Institute (TSRI) has been awarded a $6.6 million, 5-year grant by the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID) to develop a vaccine that protects against all ebolaviruses.

“This award will enable us to address a pressing global public health need, namely a single vaccine that can protect against all ebolaviruses,” stated IBT’s CSO, M. Javad Aman, Ph.D., who is co-principal investigator for the collaboration. “To meet this challenge, we have assembled a unique team of experts in immunogen design, structural biology, vaccine development, and animal models of filovirus infection.”

Filoviruses, including Ebolavirus, Sudan ebolavirus, Bundibugyo ebolavirus, and Marburg marburgvirus, cause hemorrhagic fever in humans, and infection is lethal in 40% to 90% of cases. The most recent Ebolavirus outbreak in West Africa was caused by the Zaire ebolavirus (EBOV) and led to 29,000 infections and more than 100,000 deaths. A single glycoprotein expressed on the filovirus surface mediates infection and is the primary target for vaccine development.

Structural differences in surface glycoproteins between viruses mean that current EBOV vaccine development programs are not generally not designed to protect against other filoviruses, but the team at IBT and TSRI has identified broadly neutralizing antibodies that may protect against all ebolaviruses.

The NIAID-funded project will use the EBOV glycoprotein as a foundation for the rational design of pan-Ebolavirus vaccine candidates that can elicit broadly protective immune responses targeting structural sites that are shared between the different viral glycoproteins. The aim is to develop and test immunogens that can be progressed into advanced preclinical studies. IBT says it then projects moving the most promising candidates into the clinic.

“A novel aspect of the program will be the use of state-of-the-art imaging and computational approaches,” stated co-principal investigator Erica Ollmann Saphire, Ph.D., at TSRI. “This design work will help us craft a vaccine to steer the immune response in the right directions.”

“We are excited to participate in this collaboration and to test novel immunogen design strategies for their ability to focus antibody responses to conserved epitopes on ebolaviruses,” added William Schief, Ph.D., who is also a TSRI co-principal investigator for the program. “This will be a fantastic test for structure-based vaccine design, and it may give us insights on how to make vaccines for other more variable viruses.”

The collaboration will also involve investigators at the Albert Einstein College of Medicine (Bronx, NY) the US Army Medical Research Institute of Infectious Diseases (USAMIID; Frederick, MD), the Public Health Agency of Canada (Winnipeg, Manitoba), and the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, CA.

IBT is focused on the discovery and development of vaccines and therapeutics for emerging bacterial and viral infectious diseases, including pan-filovirus immunotherapeutics and vaccines. The firm works closely with U.S. government agencies including the NIAID, National Cancer Institute, Department of Defense, and USAMRIID.

Just last month, IBT reported that its partnership with the Albert Einstein College of Medicine received Phase II of a small business technology transfer (STTR) grant from the NIAID to continue the development of bispecific antibodies targeting multiple broadly neutralizing epitopes on filovirus glycoproteins. During Phase I of the program the partners generated a lead candidate that was shown to provide protection against Ebolavirus and Sudan ebolavirus, and neutralize all ebolaviruses. Phase II of the project will encompass antibody manufacture in CHO cells and evaluation in nonhuman primates.

In May, IBT reported publication in the journal Cell of nonhuman primate studies demonstrating the ability of an antibody candidate designated CA45 to block cells from infection by EBOV, Sudan ebolavirus, and Bundibugyo ebolavirus.

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Related questions

01How stable is the antibody?

A crucial question often addressed during preclinical development focuses on the in vivo stability of therapeutic antibodies. Increasing the half-life of a therapeutic antibody has several benefits ranging from higher treatment efficacy to increased advantages for the patients who will have a fewer number of therapy sessions and a reduced cost. Given these compelling benefits, following the identification of therapeutic antibodies with the desired specificity, developers usually subject them to a refinement step to increase their stability. This process is often hindered by the lack of reliable experimental tools to predict the half-life of antibodies in patients. The major hurdle of using mouse models to predict antibody stability in the serum lies in the way immunoglobulin proteins are processed by the organism. In mammals, most proteins circulating in the serum undergo constant uptake by endothelial cells and are routed through the endosomes to the lysosomal compartment for degradation. In the endosomes, immunoglobulin G (IgG) proteins are recognized and bound by a transmembrane protein, called the neonatal Fc receptor (FcRn), which mediates their recycling to the plasma membrane and subsequent release back into the serum. As a result, the half-life of IgGs are significantly extended by this mechanism. Since most therapeutic antibodies belong to the IgG class, this recycling system is very relevant for their relative stability in the body. Remarkably, the relative affinity between IgGs and FcRn is extremely disparate between different species, with the mouse receptor showing a much higher affinity than its human counterpart.

Source: www.genengnews.com ↗

02Undruggable or unscreenable?

Another obstacle to discovering new PPI inhibitors is the lack of libraries designed to hunt for them, points out Philippe Roche, PhD, senior scientist at the Integrative Structural and Chemical Biology team at the Cancer Research Center of Marseilles, France. “If you screen PPIs using libraries that were designed for kinases or GPCRs, that’s why you don’t get a lot of good results,” he says. To that end, his group began assembling a library focused on orthosteric inhibitors of PPIs. The result was 2P2Idb, a hand-curated, structural database cataloguing orthosteric inhibitors of PPIs for which the interface had been 3D characterized. From analyzing these known PPI inhibitors, and what structures they had in common, Roche and his colleagues developed a model to predict whether compounds would likely inhibit PPIs. Using this method, 2P2Idb creates an enriched screening library that dramatically increases the hit rate compared to standard libraries. Having proven their success with a small library of 1600 compounds, they are in the process of expanding the library to 10,000 compounds. Once that’s published, “the idea is to make this library available to labs around the world,” Roche says. “We will provide the library free of charge for people to be able to screen PPI targets.”

Source: www.genengnews.com ↗

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