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Permeon Biologics touts discovery of a new class of human proteins that go above and beyond
by Kelsey Kaustinen  |  Email the author


CAMBRIDGE, Mass. —Biopharmaceutical company Permeon Biologics recently announced the discovery of a new class of human "supercharged" proteins known as Intraphilins. These proteins have a specific structure as well as a very strong positive charge, the company says, which enables intracellular movement, allowing the Intraphilins to penetrate and operate inside of cells. This could grant researchers the ability to target proteins that exist only inside the cell.
The results of the discovery were published online in July in Chemistry & Biology by Dr. David R. Liu and his colleagues. Liu is Permeon's scientific founder and scientific advisory board chairman, professor of chemistry and chemical biology at Harvard University and investigator at the Howard Hughes Medical Institute.  
"The data show that naturally supercharged Intraphilin proteins already exist within the human body and can enable the delivery of protein biologics into mammalian cells in vivo," said Liu in a press release. "Intraphilins are now being developed as a new class of human protein therapeutics to access previously undruggable intracellular target proteins and pathways."
Intraphilins exist throughout the body, inside the cell, in various compartments, on the surface or outside of cells. They have very charged positive amino acids on their surface, and function in a variety of ways: as nucleic acids binding proteins, signaling molecules and even as transcription factors.  
"The structure and the charge associate with the surface of cells in a multivalent way, so it stimulates the cells to take up these Intraphilins," says Dr. Alex Franzusoff, president and board director of Permeon. "It's important that it has structure and shape to it so that the cell can interact with it from many points of contact."
In addition, using an Intraphilin doesn't necessarily mean using the entire protein, Franzusoff notes, as it is the section with the structure and the charge that are important. Intraphilins and the small molecules currently in use can be compared holding a basketball with both hands or spinning it on one finger, Franzusoff explains. Small molecules are generally used to bind to one protein on the surface of a cell in order to deliver their payload, similar to spinning a basketball on one finger. Intraphilins' properties compare to the many-fingers approach, allowing for a greater surface area of contact and prompting cells, when they sense an Intraphilin, to take it up rapidly and potently. Rather than serving as a delivery option or vehicle themselves, Intraphilins confer their ability for intracellular movement to the biologics or antibodies they are fused with.  
To examine the Intraphilins' potential, Liu and his colleagues tested whether the proteins could enable active enzymes in adult mice to function in the retina, pancreas and white adipose tissues. They fused Intraphilins to Cre recombinase, an enzyme that serves as a mediator in DNA splicing within the nuclei of cells, then injected them into mice. Each fused pair demonstrated DNA splicing activity within the nuclei of cells in the tissues that were tested. The results are particularly encouraging since protein biologics, despite being one of the most powerful options for treatment, are usually unable to enter cells. In fact, the Intraphilins enabled internalization of the proteins with up to 40-fold higher potency than cell-penetrating peptides.  
"This potent ability to target and treat the source of disease within the cell cytoplasm and other intracellular compartments holds promise to address a vast new spectrum of intracellular disease targets," said Franzusoff in a press release. "First-generation approaches to intracellular biologics, such as cell-penetrating peptides, have not realized their full potential due to limited uptake of larger macromolecules into cells and limited tolerability."  
As there are more than 1,500 intracellular target proteins within cells that are currently considered undruggable, these Intraphilins could enable much more specific protein targeting. Rather than seeking to shut down a whole kinase, fusing protein biologics with Intraphilins can allow the potent biologics to simply interfere with one target molecule. This could allow for increased selectivity and ways to "intervene or activate by virtue of protein-protein interaction," Franzusoff explains.
Permeon is currently working on the proof-of-concept data, Franzusoff says, in order to "demonstrate the efficacy with intracellular monoclonal antibodies and move…towards developing a clinical program around the targets that we are in the process of evaluating." As for which diseases or biologics Permeon will be looking at first in conjunction with the Intraphilins, Franzusoff says it is "a little bit early for us to speculate."  
"We're definitely paying attention to some of the things that would make the best early bets, and we will build an internal pipeline around the things that will give us the cleanest proof-of-concept," says Franzusoff. "But we'll also be partnering to expand the platform against a variety of different targets…There's a possibility to go after many different applications, but we are very focused and we will be choosing amongst the ones that will be the most clear-cut demonstrations that this can really open up an entire new drug development field."  
The aforementioned paper, "A Class of Human Proteins that Deliver Functional Proteins into Mammalian Cells In Vitro and In Vivo," was published both online and in the July 29 print edition of Chemistry & Biology. The other authors include James J. Cronican, Erin M. May, Allen F. Shih, David B. Thompson, Kevin T. Beier, Constance L. Cepko, Tina N. Davis, Jen-Chieh Tseng, Weida Li, Andrew L. Kung and Qiao Zhou.     

Code: E08241104



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