TSRI and Calibr sign strategic affiliation to accelerate the development of new medicines

Deal between the two non-profit research organizations lays the foundation for a new ‘evergreen’ biomedical research model

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LA JOLLA, Calif.—On Oct. 20, two powerhouse non-profit life-sciences research organizations—The Scripps Research Institute (TSRI) and the California Institute for Biomedical Research (Calibr)—revealed that they had signed a strategic affiliation that, as they put it, “combines the two organizations into a new biomedical research entity with the tools and know-how to rapidly translate its scientific discoveries into life-saving medicines for the public benefit.”
What TSRI and Calibr aim to do is to integrate basic scientific and translational research with an eye toward cutting the costs and shortening the timelines associated with the early stages of drug development. This, in turn, can lead to the creation of a sort of “evergreen” approach to biomedical research—a “self-sustaining model for non-profit research in which drug development successes drive the funding of new scientific discoveries and medicines many years into the future,” as the TSRI/Calibr announcement said.
Of course, it doesn’t hurt the process that both of these non-profit organizations are led by Dr. Peter Schultz, and the union of the two is expected to provide the ability to rapidly move the basic scientific research carried out at TSRI into Calibr, whose expertise and infrastructure can accelerate drug development from discovery through early clinical trials, complementing the pharmaceutical industry's increasing focus on the later stages of clinical development.
“The affiliation between TSRI and Calibr is the first of its kind. Unlike other research institutes and universities that have sought to establish translational capabilities within academic centers, we aren’t building from scratch—rather, we are integrating the strengths of two proven non-profit organizations, enabling TSRI to remain committed to basic biological and chemical discovery and the understanding of disease processes, while turning these insights into innovative new medicines for unmet needs ranging from cancer and degenerative disease to childhood and neglected diseases through the affiliation with Calibr,” said Schultz. “Ultimately, I believe this ‘bench-to-bedside’ model has the potential to become self-sustaining, with the value we create being reinvested back into research, education and additional clinical studies.”
As part of the formal affiliation, the two organizations will now share a combined board of directors, as well as scientific and administrative resources that will be consolidated over time. Both institutes will continue to collaborate with their other partners in the academic and commercial sectors.
“I want my work to have an impact on the lives of people suffering from life-threatening diseases, and the TSRI integration with Calibr provides an important mechanism for moving molecules faster and further along the research to development continuum, while also creating additional value for TSRI and Calibr,” said Dr. Jeff Kelly, the Lita Annenberg Hazen Professor of Chemistry and chairman of the Department of Molecular Medicine at TSRI.
Each of the 10 regulatory agency-approved medicines emerging from TSRI took an average of more than 20 years to move from drug discovery to market availability. The new affiliation between TSRI and Calibr aspires to accelerate that timeline, as well as to increase the number of basic science discoveries that are translated into first-in-class drugs.
“The partnership with TSRI is critical to our long-term vision for Calibr,” said Dr. Matt Tremblay, Calibr’s chief operating officer. “We’re thrilled to work alongside TSRI’s world-class faculty and bring Calibr’s capabilities and focus to bear in creating a self-renewing source of new drug discovery opportunities well into the future.”
The two organizations have already successfully collaborated on several research programs in recent years, including the development of an antibody engineering platform that could improve treatments for chronic diseases such as diabetes and chronic obstructive pulmonary disease, as well as innovative immune therapies for the treatment of cancer. These collaborations have led to several candidate therapies, two of which Calibr has partnered with major pharmaceutical companies.
Moreover, the two organizations say, these collaborations are providing a unique training environment for students and fellows at the interface of basic and translational research, resulting in high-impact publications, and preparing them to tackle some of the most important biomedical challenges in academia and industry.
In other recent TSRI news, researchers there say they have discovered one reason why success has so far been elusive in developing a vaccine against the hepatitis C virus (HCV).
Using an array of techniques for mapping tiny molecular structures, the TSRI scientists analyzed a lab-made version of a key viral protein, which has been employed in some candidate HCV vaccines to induce the body’s antibody response to the virus. The researchers found that the part of this protein meant as the prime target of the vaccine is surprisingly flexible. Presenting a wide variety of shapes to the immune system, it thus likely elicits a wide variety of antibodies, most of which cannot block viral infection.
“Because of that flexibility, using this particular protein in HCV vaccines may not be the best way to go,” said Mansun Law, co-senior author and a TSRI associate professor.
“We may want to engineer a version that is less flexible to get a better neutralizing response to the key target site and not so many off-target responses,” said co-senior author Ian A. Wilson, who is TSRI’s Hansen Professor of Structural Biology and a member of the Skaggs Institute for Chemical Biology at TSRI.
The Law and Wilson laboratories have been working together in recent years to study HCV’s structure for clues to successful vaccine design. In 2013, for example, the team successfully mapped the atomic structure of the viral envelope protein E2, including the site where it binds to surface receptors on liver cells.
Because this receptor-binding site on E2 is crucial to HCV’s ability to infect its hosts, it has an amino-acid sequence that is relatively invariant from strain to strain. The receptor-binding site is also relatively accessible to antibodies, and indeed many of the antibodies that have been found to neutralize a broad set of HCV strains do so by targeting this site.
For all these reasons, HCV’s receptor-binding site has been considered an excellent target for a vaccine. But although candidate HCV vaccines mimicking the E2 protein have elicited high levels of antibodies against the receptor-binding site, these antibody responses—in both animal models and human clinical trials—have not been very effective at preventing HCV infection of liver cells in laboratory assays.
To understand why, the Law and Wilson laboratories teamed up with TSRI Associate Professor Andrew Ward and used electron microscopy and several other advanced structural analysis tools to take a closer look at HCV’s E2 protein, in particular the dynamics of its receptor binding site. Their investigations focused on the “recombinant” form of the E2 protein, produced in the lab and therefore isolated from the rest of the virus. Recombinant E2 is a prime candidate for HCV vaccine design and is much easier to purify and study than E2 from whole virus particles.
One finding was that recombinant E2, probably due to its many strong disulfide bonds, has great structural stability, with an unusually high melting point of 85°C. However, the TSRI scientists also found evidence that, within this highly buttressed construction, the receptor binding site portion is extraordinarily loose and flexible in the recombinant protein.
Prior studies have shown that HCV’s receptor binding site adopts a narrow range of conformations (shapes) when bound by virus-neutralizing antibodies. A vaccine that elicited high levels of antibodies against only these key conformations would in principle provide effective protection. But this study suggests that the E2 protein used in candidate vaccines displays far too many other binding-site conformations—and thus elicits antibodies that mostly do nothing to stop the actual virus.
Law and Wilson and their colleagues plan to follow up by studying E2 and its receptor binding site as they are presented on the surface of the actual virus. They also plan to design a new version of E2 or even an entirely different scaffold protein, on which the receptor binding site is stabilized in conformations that will elicit virus-neutralizing antibodies.

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