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Chance and Prepared Minds Lead from Lab to New Drug Development

Science rarely moves in a straight line—like a good page-turner, the story of scientific discovery is often full of twists and turns, dead ends and red herrings, and then a sudden burst of insight, sometimes from an unexpected source. For all the painstakingly prepared proposals and long hours spent at the lab bench or clinic, scientists often speak of serendipity as playing an essential part in their tales of scientific discovery.  And these discoveries, originally directed at a specific biomedical question, can at times inspire an answer to another, seemingly unrelated problem. One story with all of these elements of surprise is that of an unexpected scientific journey spanning more than 2 decades. It begins with a basic research discovery in adult intestinal cells and arrives those decades later at new opportunities for improved treatments against diseases at multiple sites throughout the human body, including two recently approved drugs for hemophilia.

From Failure, Fortune

On July 22nd, 1992, NIDDK grantee Dr. Richard Blumberg was working in his lab when his postdoctoral fellow came to express frustration over a failed negative control in one of his experiments. The fellow had been conducting experiments in an adult human intestinal cell line with immune molecules called antibodies, which attach to proteins on the cell surface.  His negative control antibody was designed not to bind the cellular proteins that the experimental antibody was binding. But the control antibody had latched on instead to some unknown protein.

“Chance favors only the prepared mind,” is a saying attributed to the microbiologist Louis Pasteur. When Dr. Blumberg looked at the result, in an instant his mind returned to his own postdoctoral training, working with a type of protein on cell surfaces called a major histocompatibility complex (MHC) class I molecule. MHC class I molecules are displayed on the cell surface to help the immune system distinguish healthy from infected cells. He experienced a flash of recognition—the control antibody was likely attaching itself to a related molecule known as the neonatal Fc receptor, or “FcRn.” But, as the name of the molecule suggests, at the time it had only been found in newborn rodents, not in their adult cells, and the molecule had never been found in humans.

First discovered in the mid-1960s, FcRn was known to interact with a portion of the immunoglobulin G (IgG) antibody called the Fc domain, controlling transport of IgG across intestinal epithelial cell layers in early life in rodents. IgG is the most abundant type of antibody in the blood and extracellular spaces in internal tissues, including portions of the intestines, where it helps protect against infection. Newborn rodents receive IgG mainly from their mothers’ milk via the aforementioned process, while in humans, IgG is transferred from mother to fetus across the placenta to confer protection.

In the years following that “failed” experiment in 1992, Dr. Blumberg’s group and others confirmed that the “neonatal” Fc receptor was indeed a misnomer. The receptor continues to be produced into adulthood in a number of cell types throughout the human body. In the 1990s, they published their findings confirming FcRn in adult liver hepatocytes and intestinal epithelial cells, followed by reports in lung epithelial cells, endothelial cells that line blood vessels, and, most importantly, multiple types of cells that are involved in immunity.

They and others also uncovered a broad range of functions carried out by FcRn in humans, including carrying IgG across the placenta, transporting IgG back and forth across mucosal layers such as the intestinal and lung epithelial barriers, delivering IgG bound to a protein from an invading pathogen to alert local immune cells, and controlling the movement of IgG molecules in the circulation. The interaction between FcRn and IgG was found to give the antibody greater stability by delaying its degradation within cells and recycling it back into the circulation. This explains why IgG lasts so much longer in the bloodstream than other proteins—for weeks rather than days or even minutes.

Translating Laboratory Successes into Clinical Solutions

For more than 2 decades, the NIDDK has supported Dr. Blumberg’s research investigating and translating that important initial discovery of FcRn in adult human cells. A pilot grant from the NIDDK-supported Harvard Digestive Diseases Center enabled the lab’s first experiments to pursue this finding in the early 1990s, collecting evidence confirming FcRn’s presence and function in different human cell types. After that, the group had enough data assembled to successfully apply for an R01 grant awarded through the NIDDK in 1997, allowing them to delve more deeply into the immunology and cell biology of FcRn’s functions in transporting IgG.

From that first moment of discovery in 1992, Dr. Blumberg recognized the translational potential of the FcRn-IgG system in adult humans. This system had the unique ability to move large molecules across mucosal layers in the intestine and lung, a property that would theoretically enable oral or inhaled delivery of drugs that would otherwise be deliverable only by injection. They started filing for a patent, which was issued in 1995.

The finding in 1996 by other groups of FcRn’s role in recycling IgG in the bloodstream further deepened their interest in this system for improving drug delivery. By tethering large macromolecules, such as drugs, just to the Fc piece of IgG, which would then be transported through the body to their site of action and repeatedly recycled by the FcRn, they could achieve longer-acting drugs. An added benefit discovered by another group was that, because the body recognizes and tolerates the Fc portion of the IgG antibody, molecules fused to Fc were less likely to set off an adverse reaction by the immune system and thus would presumably be safer to use.

In 1999, Dr. Blumberg and others launched a new pharmaceutical company to pursue translation of this work. Along the way, Dr. Blumberg collaborated with many other “prepared minds” who collectively helped fuel further discoveries and move the science forward to translation in the clinic. They included his co-investigator on the R01 grant, Dr. Wayne Lencer, who brought expertise in cell biology; Dr. Blumberg’s brother, businessman and physician Dr. Laurence Blumberg, who helped with the business plan and funding for their fledgling company; Dr. Tom Maniatis, a molecular biologist and cofounder of other pharmaceutical companies, who helped Dr. Blumberg and his colleagues to develop the new company; and others in academia and industry.

In 2004, Dr. Blumberg and his collaborators at the newly formed company published another important discovery. They were able to create a unique Fc fusion protein with erythropoietin (EPO), a naturally occurring hormone sometimes used to treat anemia, which could be delivered in aerosol form through a tube in the lungs of a pre-clinical animal model in non-human primates. They found that, by linking only one EPO molecule to two Fc domains, rather than the two molecules used in the past, the resulting fusion protein, which they called a “monomeric” Fc fusion protein, delivered by aerosol was longer-acting and more effective, similar to EPO injections in humans.

The team decided to focus their attention next on hemophilia, due to a pressing need for more longer-acting drugs. Adults and children with hemophilia A or B are deficient in a specific clotting factor in the blood, either Factor VIII or IX, respectively, which puts them at risk for bleeding episodes. However, replacing these factors was no easy matter. Due to their large size and short half-lives in the circulation, they were difficult to deliver in a form that was easy to use. Moreover, existing drugs required frequent intravenous infusions as needed, at least every few days, to prevent complications from bleeding episodes, such as severe bruising and bleeding into joints that sometimes leaves individuals crippled. This is especially problematic for children, limiting the use of these factors during one of the most vulnerable periods of life. Further, these factors also sometimes elicited a harmful immune reaction in patients, though another group had recently shown how IgG-accompanied Factor VIII did not elicit such a response.

In 2007, the company that Dr. Blumberg helped found was sold to a larger pharmaceutical company, which used the Fc fusion technology and knowledge generated by Dr. Blumberg and colleagues to develop two long-acting Fc-fusion Factor VIII and Factor IX therapeutic agents for hemophilia A and B, respectively. Like the Fc-fusion EPO drug for anemia, these agents were designed with only one drug molecule attached to two Fc domains for greater staying power and effectiveness. The company performed clinical trials on these drugs, showing they were safe and effective. In 2014, these drugs were approved by the U.S. Food and Drug Administration (FDA), with AlprolixTM released as a hemophilia B treatment in March followed by EloctateTM for hemophilia A in June. EloctateTM allows patients with hemophilia A to go 3 to 5 days between infusions, while AlprolixTM extends the time between treatments even longer, up to 1 to 2 weeks.

Bright Horizons for Better Treatments

In addition to the hemophilia drugs based on work by Dr. Blumberg and colleagues, Fc-fusion proteins developed by other groups have been approved by the FDA since the 1990s for the treatment of other diseases, largely autoimmune in nature, such as rheumatoid arthritis and psoriasis. Antibody-based therapeutics that depend on FcRn-based biology have also shown promise against a host of other diseases, including inflammatory bowel disease, colorectal cancer, and even protection against infectious diseases such as HIV-AIDS. These versatile proteins might also be tested for other uses, including as an antidote for an adverse drug reaction and as a means to clear radioactive materials administered for imaging.

Although the hemophilia drugs based on Dr. Blumberg’s and others’ work are delivered by injection, Fc-fusion drugs have the potential for less-invasive delivery in the future based on their unique ability to interact with the FcRn and cross mucosal barriers like the lung and intestine. For example, patients might one day use an inhaler to deliver an Fc-fusion drug through the lung epithelial tissue to reach other disease sites throughout the body. This concept has been enabled by the team Dr. Blumberg and his colleagues assembled, as shown by successful completion of a phase I study of an inhaled Fc-fusion protein containing EPO. Researchers who have been inspired by Dr. Blumberg’s work and with whom Dr. Blumberg has collaborated are also looking into using Fc fragment-coated nanoparticles as a vehicle for oral delivery of drugs that are currently administered by injection, such as insulin for diabetes, thereby improving patient comfort and compliance.

Research grants to Dr. Blumberg’s group and others are continuing to support exploration of the basic biology of the Fc system and its yet-unknown discoveries, which could lead to additional clinical technologies and therapies. All in all, the future looks bright for one “failed” laboratory experiment to continue to yield fruits that benefit patients for years to come.

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