Permeon Biologics touts discovery of a new class of human proteins that go above and beyond

Intraphilins now being eyed for development as human protein therapeutics to access previously undruggable intracellular target proteins and pathways

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CAMBRIDGE, Mass.—Biopharmaceutical company Permeon Biologicsrecently announced the discovery of a new class of human "supercharged" proteinsknown as Intraphilins. These proteins have a specific structure as well as avery strong positive charge, the company says, which enables intracellular movement, allowing theIntraphilins to penetrate and operate inside of cells. This could grantresearchers the ability to target proteins that exist only inside the cell.
The results of the discovery were published online in Julyin Chemistry & Biology by Dr. DavidR. Liu and his colleagues. Liu is Permeon's scientific founder andscientific advisory board chairman, professor of chemistry and chemical biologyat Harvard University and investigator at the Howard Hughes Medical Institute.
"The data show that naturally supercharged Intraphilinproteins already exist within the human body and can enable the delivery ofprotein biologics into mammalian cells invivo," said Liu in a press release. "Intraphilins are now being developedas a new class of human protein therapeutics to access previously undruggableintracellular target proteins and pathways."
Intraphilins exist throughout the body, inside the cell, invarious compartments, on the surface or outside of cells. They have very chargedpositive amino acids on their surface, and function in a variety of ways: asnucleic acids binding proteins, signaling molecules and even as transcriptionfactors.
"The structure and the charge associate with the surface ofcells in a multivalent way, so it stimulates the cells to take up theseIntraphilins," says Dr. Alex Franzusoff, president and board director ofPermeon. "It's important that it has structure and shape to it so that the cellcan interact with it from many points of contact."
In addition, using an Intraphilin doesn't necessarily meanusing the entire protein, Franzusoff notes, as it is the section with thestructure and the charge that are important. Intraphilins and the smallmolecules currently in use can be compared holding a basketball with both handsor spinning it on one finger, Franzusoff explains. Small molecules aregenerally used to bind to one protein on the surface of a cell in order todeliver their payload, similar to spinning a basketball on one finger. Intraphilins'properties compare to the many-fingers approach, allowing for a greater surfacearea of contact and prompting cells, when they sense an Intraphilin, to take itup rapidly and potently. Rather than serving as a delivery option or vehiclethemselves, Intraphilins confer their ability for intracellular movement to thebiologics or antibodies they are fused with.
To examine the Intraphilins' potential, Liu and hiscolleagues tested whether the proteins could enable active enzymes in adultmice to function in the retina, pancreas and white adipose tissues. They fusedIntraphilins to Cre recombinase, an enzyme that serves as a mediator in DNAsplicing within the nuclei of cells, then injected them into mice. Each fusedpair demonstrated DNA splicing activity within the nuclei of cells in thetissues that were tested. The results are particularly encouraging sinceprotein biologics, despite being one of the most powerful options fortreatment, are usually unable to enter cells. In fact, the Intraphilins enabledinternalization of the proteins with up to 40-fold higher potency thancell-penetrating peptides.
"This potent ability to target and treat the source ofdisease within the cell cytoplasm and other intracellular compartments holdspromise to address a vast new spectrum of intracellular disease targets," saidFranzusoff in a press release. "First-generation approaches to intracellularbiologics, such as cell-penetrating peptides, have not realized their fullpotential due to limited uptake of larger macromolecules into cells and limitedtolerability."
As there are more than 1,500 intracellular target proteins withincells that are currently considered undruggable, these Intraphilins couldenable much more specific protein targeting. Rather than seeking to shut down awhole kinase, fusing protein biologics with Intraphilins can allow the potentbiologics to simply interfere with one target molecule. This could allow forincreased selectivity and ways to "intervene or activate by virtue ofprotein-protein interaction," Franzusoff explains. 
Permeon is currently working on the proof-of-concept data,Franzusoff says, in order to "demonstrate the efficacy with intracellularmonoclonal antibodies and move…towards developing a clinical program around thetargets that we are in the process of evaluating." As for which diseases orbiologics Permeon will be looking at first in conjunction with theIntraphilins, Franzusoff says it is "a little bit early for us to speculate."
"We're definitely paying attention to some of the thingsthat would make the best early bets, and we will build an internal pipelinearound the things that will give us the cleanest proof-of-concept," saysFranzusoff. "But we'll also be partnering to expand the platform against avariety of different targets…There's a possibility to go after many differentapplications, but we are very focused and we will be choosing amongst the onesthat will be the most clear-cut demonstrations that this can really open up anentire new drug development field."
The aforementioned paper, "A Class of Human Proteins thatDeliver 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 otherauthors 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.

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