When she was just five years old, Emily Whitehead was diagnosed with acute lymphoblastic leukemia. It’s the most common variety of childhood cancer, and hers proved particularly resilient in the face of conventional treatments. After Emily relapsed twice, her desperate parents enrolled her in a clinical trial for a promising new therapy that genetically reprograms white blood cells so they can better recognize and kill cancer cells.
It was the first time the experimental therapy had been used on a child, and the side effects nearly killed her. But ultimately it worked. In 2012, two years after her diagnosis, Emily’s cancer went into complete remission. However, the treatment severely weakened her immune system, permanently. That’s a comparatively small price to pay to save a child’s life; most parents would make that trade-off. But if scientists at the nonprofit California Institute for Biomedical Research (Calibr) have their way, future children like Emily will have access to a version of the treatment that doesn’t cause that kind of permanent damage—or have life-threatening side effects.
Calibr is the brainchild of its director, chemist and entrepreneur Peter Schultz, who aims to speed up the drug-discovery process by combining the strengths of the corporate pharmaceutical industry with the basic research conducted at universities. Headquartered in La Jolla, California, Calibr is developing drug therapies for an astonishing range of conditions: not just cancer but also multiple sclerosis, osteo-arthritis, malaria, and Parkinson’s, to name a few.
“Nature solves a lot of problems in biology by creating large numbers of candidate proteins or antibodies and selecting one that works,” Schultz says. “Whereas chemists tend to rationalize design. We have brought in this idea of creating large chemistry diversity and simply finding the right key in the haystack to solve problems.”
Schultz’s strategy: Do the basic research, identify promising molecules for targeting specific conditions, and then test those using high-throughput systems to find the best match. He calls this a “bench to bedside” model, and it lies at the heart of Calibr’s approach to drug discovery and development.
“Our goal is getting interesting initial discoveries from basic research through screening and animal testing to eventually get to a drug candidate, and to do that with many different types of drugs,” says Arnab Chatterjee, Calibr’s vice president of medicinal chemistry.
In this, Calibr differs from the pharmaceutical industry, which tends to be more risk-averse and selective in terms of where it invests its capital. But while the typical drug takes over $2.5 billion and about 12 years to develop, from discovery to approval, Calibr brought one of its new drugs to trial in just three years, according to Schultz. That translated into substantial savings. Since its founding seven years ago, Calibr has already brought three molecules to clinical trial, with more in the pipeline. One of the molecules in its pipeline is a cancer therapy that would have helped little Emily Whitehead.
OLDIES BUT GOODIES
After earning a PhD in chemistry from Caltech in 1984, Schultz soon made a name for himself as a leading chemist at the University of California, Berkeley. In addition to conducting research on reprogramming genetic code, he helped pioneer the field of combinatorial chemistry, in which millions of molecules can be synthesized and tested for interesting bioactive properties at a fraction of the time and cost. His lab developed the first libraries of materials, including high-temperature superconductors and phosphors.
“He had a vision that the way to accelerate discovery was to look at large chemical libraries,” says Peter Dervan, a biochemist at Caltech who mentored Schultz there.
That work got him involved in the early days of the Silicon Valley biotech boom. He helped form a number of successful companies, which read like a who’s who of California biotech: Symyx Technologies, Syrrx, Kalypsys, Ambrx, and Wildcat Discovery Technologies, to name a few.
In 1999, Schultz moved his Berkeley lab to Scripps Research (formerly the Scripps Research Institute) in La Jolla. His expertise in both basic research and technological innovation meshed perfectly with the institute’s mission of funding research to speed up drug discovery. Scripps Research was founded in 1924 by the philanthropist Ellen Browning Scripps, who had been inspired by the discovery of insulin to treat diabetes a few years before. (The Scripps family also helped establish the San Diego Zoo and the Scripps Institution of Oceanography, a separate entity affiliated with the University of California, San Diego. Disclosure: the Hearst Foundations, of which Alta editor and publisher William R. Hearst III is a director, has provided financial support to Scripps Research.)
Around the same time, the Novartis Research Foundation was looking for just the right person to lead its new Genomics Institute (GNF) in researching new drug targets, and it recruited Schultz. He helped create a state-of-the-art high-throughput screening system to scan vast libraries with a million or more chemical and genomic compounds. One of the reasons large pharmaceutical companies must be so selective in their investments is that it can be expensive and time-consuming to screen compounds in the early stages. With this new equipment, it costs significantly less to screen a compound, so it’s possible to test many more of them at a fraction of the cost.
Schultz ran GNF for more than 10 years, while maintaining his research lab at Scripps. According to Schultz, in that time, Novartis’s total investment in GNF grew from an estimated $100 million over a 10-year period to well over $1 billion. When Novartis brought the independent GNF back into the corporate fold, Schultz decided he would use the tools and expertise he had developed during his tenure there to do drug discovery in the nonprofit sector. In 2012, he founded Calibr, to build similar capabilities and processes there.
The innovations Calibr heralded led to Schultz becoming the CEO of Scripps Research in 2015—and the president the following year. His mandate: implement more of a systems approach to drug discovery and development by joining Scripps with Calibr, to take full advantage of their respective strengths.
New drug discoveries often start in academic labs, with scientists making breakthroughs that hold the potential for future pharmaceutical applications—identifying a key cell receptor for targeted drug delivery, for instance. The university may then form a startup, funded by outside investors, to perform the necessary preclinical work. If it succeeds, the startup will partner with a large pharmaceutical company for clinical trials—a lengthy and very expensive process. Eventually, if all goes well, the new drug will receive FDA approval and enter the market.
With Calibr’s bench-to-bedside approach, Scripps scientists make the pioneering discoveries and pass those insights on to Calibr for rapid screening and preclinical testing. There’s a financial benefit, as Scripps and Calibr get to hang on to the intellectual property rights for a longer stretch of the development pipeline, giving them a larger financial stake in the final product. “You have a constant input of interesting new ideas and discoveries, and you also have the ability to translate those discoveries into new medicines,” says Schultz. “And the value creation goes up almost exponentially as you go from early-stage to clinically tested molecules.”
This is a significant twist on the pharmaceutical industry’s reliance on academics to discover new ways to treat disease. But “academics are driving most of the discoveries on the biological mechanisms behind the causes of disease, defining the new pharmacological targets, and, more recently, also finding the molecules that can modulate those targets,” says Emilio Diez Monedero, a drug discovery consultant and entrepreneur, and a board member at the Society for Laboratory Automation and Screening. Calibr is just one more step forward in that regard.
High-throughput screening was one innovation. Schultz’s next one was pointing such screening at existing drugs or compounds already shown to be safe for humans, with the aim of finding new applications for them—especially molecules that were off patent or could be licensed via collaborations. For instance, Calibr partnered with DuPont to test its collection of insecticides and found a potent antimalarial molecule that lasts up to four months in the body and kills the type of mosquito that carries the parasite. It could potentially reduce malarial outbreaks by up to 97 percent, according to Schultz. And it’s based on a medication given to dogs to ward off fleas and ticks and hence Lyme disease. (Schultz cautions that you absolutely should not be taking your dog’s flea and tick medication.)
One older compound currently going through clinical trials is clofazimine, a decades-old molecule originally commercialized by Novartis as a dye that also happens to be a very good treatment for the rare disease leprosy. Calibr found it to be effective against cryptosporidiosis, a leading cause of childhood diarrhea. Calibr researchers are running a study with local clinics and academic labs in Malawi that uses Calibr’s data models to test the compound with adults who are HIV positive and suffering from cryptosporidiosis. “Usually in developing countries, we work with clinics or labs that have access to parasites in patients, but not to screening collections,” says Chatterjee. “That’s where Calibr and Scripps can have an impact. It’s part of the reason we built this compound collection.”
Another older compound is auranofin, developed in the 1960s to treat rheumatoid arthritis. The drug has since been eclipsed by more effective treatments for the condition, most notably Humira. But Calibr scientists have found that auranofin is very effective against tuberculosis, which is still rampant in developing countries.
Yet a third compound to enter clinical trials is KA34, a potential stem cell–based treatment for osteoarthritis. In the United States alone, approximately 27 million people suffer from this degenerative joint disease that usually affects the knees, hips, and smaller joints in the fingers and toes. The disease breaks down the protective cartilage that covers the ends of bones and acts as a cushion between bones. The result is painful swelling, chronic inflammation, and difficulty moving the affected joints. Prescription painkillers often help, but the only true remedy is surgery.
The human body relies on a particular kind of stem cell, a chondrocyte, to make new cartilage, and Schultz envisions a day when it will be possible to simply inject a drug into the affected joint and turn a resident stem cell into a chondrocyte, which will make new cartilage. His scientists have identified KA34, which was tested successfully on rats and dogs, as a candidate. If successful in the clinical trials, KA34 would be a shining example of Calibr’s bench-to-bedside abilities.
“While [Calibr’s] approach has been very successful in generating drug candidates, these molecules are still 5 to 10 years away from being drugs,” cautions Bill Janzen, vice president of lead discovery and research operations at Ribometrix, a therapeutics company targeting small molecules for discovery. “And the failure rate during clinical trials is about 9 out of 10.”
Still, Schultz is optimistic that Calibr can take an approach similar to that for osteoarthritis with multiple sclerosis, an immune-mediated disease affecting some 2.5 million people worldwide. The symptoms and severity of the disease can vary widely in different people, but the root cause is the immune system attacking a fatty material called myelin that wraps around nerve fibers in the central nervous system like insulation to protect them. This immune system assault impairs the brain’s ability to send signals through the body. There are already good immunosuppressant drugs on the market to treat MS, but they have side effects, and the drugs do not address the root cause of the disease.
Myelin is produced by a type of cell called an oligodendrocyte, but there are few at sites in the brain with MS lesions, according to Schultz. Calibr scientists are now identifying molecules that turn stem cell precursors in the brain into oligodendroctyes. If successful, this effort would lead to a two-pronged treatment for MS, one that could tamp down the damaging immune response and replace the damaged myelin.
Calibr has even bigger ambitions for treating cancer—using its high-throughput screening capability to identify promising antibodies for an augmented form of the pioneering treatment that saved Emily Whitehead: chimeric antigen receptor (CAR) T-cell therapy. There are two types of white blood cells in the immune system that normally help protect the body against infection: T cells and B cells. Cytotoxic T cells detect and destroy invaders in the body, but abnormal B cells resulting from a blood cancer like leukemia are able to elude detection. CAR T-cell therapy uses genetic engineering to reprogram the body’s T cells to better target and eliminate those malignant cells, using the patient’s own immune system as a weapon against their cancer.
It works like this: A patient’s blood is drawn at a clinic, and the T cells are separated out and shipped to a facility. There, they are genetically engineered to attach only to a specific protein (CD19) found on the surface of B cells. The altered T cells are frozen and sent back to the hospital, where they are injected back into the patient. “Now they act like autonomous self-driven cellular enemies that not only target and destroy cancer cells inside the body, but can also divide and expand to overwhelm the cancer cells,” says Travis Young, Calibr’s director of protein sciences.
This is markedly different from typical drug therapy, in which the drug is administered, decays in concentration over time, and is gradually excreted from the body entirely. With CAR T-cell therapy, the engineered cells multiply exponentially as they encounter cancer cells. And they survive in the body for up to several years. The potential result: remission rates as high as 80 to 90 percent.
Two CAR T-cell therapies are currently on the market, specifically targeting blood cancers (leukemias and lymphomas): Kymriah, by Novartis, and Yescarta, developed by a small biotech company called Kite, since purchased by Gilead. But there’s a flip side to the therapy’s potency. CAR T-cell therapy can wipe out healthy B cells as well as cancer cells, leading to a lifelong B-cell deficiency. The condition is less severe than HIV (a T-cell deficiency), and treatments exist to supplement that deficiency.
An even more serious side effect is the one that almost killed Emily Whitehead: a toxic autoimmune inflammatory response that presents as a very high fever, nausea, and muscle pain, setting in within 12 to 24 hours of the injection. In the most serious cases, it leads to swelling of the brain—and death. It happens because the rapidly growing number of engineered T cells results in abnormally high levels of a protein called cytokine (also implicated in rheumatoid arthritis); the bigger the tumor being attacked, the higher the by-product levels of cytokine. This “cytokine storm” can be calmed with drugs, but recent studies have found that as many as 23 percent of adult subjects are affected.
Owing to these complications, the FDA has approved the treatment only for patients with specific kinds of blood cancers, when other conventional therapies have failed. So Calibr is developing an augmented version that combines the gene therapy with antibodies: a “switchable” CAR T-cell platform. Antibodies alone aren’t nearly as potent against cancer cells as the engineered white blood cells, but they also don’t trigger the same inflammatory response.
In standard CAR T-cell therapy, the cell is engineered to express a receptor on its surface that then binds directly to the tumor cell to kill it. Calibr’s approach involves augmenting the natural functions of T cells. Then an intermediary antibody molecule serves as a bridge between the T cell and the cancer cell. And because the antibody molecule is dosed separately, it’s possible to tune exactly how aggressive the engineered T cells should be after they are injected into the patient, much like with a remote-controlled light dimmer.
According to Schultz, a low dose will clear 95 percent of the tumor. Once the bulk of it is gone, switching to a higher dose will clear the rest of the tumor, with no severe inflammatory response. Antibodies linger in the body for between a couple of hours and a couple of days, depending on the dose, while the engineered T cells last for months to years—but without their initial toxicity.
Calibr’s treatment should also be less pricey than conventional CAR T-cell therapy, which currently costs about $450,000, in part because each white blood cell must be tailored for a specific kind of cancer. “We don’t need to create a new T cell every time,” says Young. “We just create a new switch molecule.” Calibr plans to start Phase 1 human clinical trials for its controllable CAR T-cell therapy by the end of this year. “We will have good indication of whether this is working or not within one to two years,” says Young. If it does work, Calibr hopes that one day the therapy might be used to treat many kinds of cancer.
RESEARCH, FUND THYSELF
Schultz hopes his vision will evolve into a new model for research funding. One reason universities tend to hand over their intellectual property to big pharmaceutical companies fairly early in the development process is that they lack the financial resources and regulatory expertise to independently get a drug approved. The companies take the drug through all the clinical trials to market, creating billion-dollar industries—and profits. But universities reap only a small percentage of those profits; most of the value created flows back to the corporate shareholders.
Schultz wants to take a few pages from Big Pharma’s playbook, shifting the focus in academic funding away from its heavy reliance on grants from federal institutions like the National Institutes of Health and the generosity of wealthy philanthropists. Merging the complementary strengths of Scripps and Calibr means that the collaboration can hang on to its IP through early-stage clinical trials, only then turning the process over to Big Pharma. That could translate into profits in the range of tens or hundreds of millions of dollars, rather than just a few million. That greater share in profits can in turn be used to build up an institution’s endowments and to fund further cutting-edge research to make even more exciting new discoveries.
“This model will provide a much larger return, to be reinvested, to public institutions,” says drug discovery consultant Diez-Monedero. “More importantly, the projects will have a much better chance of success, being less dependent on VC funding, or on the high volatility of drug development pipelines in the pharmaceutical industry. I believe we will see this new model of drug discovery and development [become] more generalized in the future, with pharma being involved only after proof of concept is achieved in human clinical trials.”
Other traditional research institutions are watching Schultz’s efforts with considerable interest, but for now few are poised to adopt such a model. While Caltech, for instance, is very interested in research that directly addresses critical health needs, and could conceivably decide to make a financial investment in building a similar effort, “I don’t think we have the preclinical regulatory expertise to be able to do this,” Caltech’s Dervan says. Schultz gained that expertise during his years at GNF, which is why Dervan thinks the Scripps-Calibr partnership has a good chance of succeeding. If it does, “then there will be generations to come after Peter, mentored by him, that will be able to run with the ball,” he says.
“The idea is that not only can you create a medicine, but you can share to a far greater degree in the value creation, and bring those resources back into your institution to make the whole thing self-sustaining,” Schultz says. “If it works, I think it will really change how universities and research institutes think about doing science.”
Jennifer Ouellette is a science writer based in Los Angeles. She wrote about gravitational waves in Alta’s Summer 2018 issue. Me, Myself, and Why: Searching for the Science of Self is her most recent book.
• 100+ interdisciplinary scientists
• $250 million in research funding from Gates Foundation, Wellcome Trust, and others
• Partnerships for preclinical and clinical development with Merck, Pfizer, and more
• 77,000-square-foot facility in San Diego
• A division of Scripps Research
• 2000+ researchers
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SOURCE: SCRIPPS RESEARCH