Permeon reveals discovery of Intraphilins as new approach to intracellular biologic drugs

(Press-News.org) Permeon Biologics, a biopharmaceutical company pioneering a novel class of intracellular protein biologics, today announced the discovery of an entirely new class of naturally occurring human supercharged proteins called Intraphilins™. The sequence and structure of these naturally supercharged human proteins enable biologic drugs to penetrate and function inside of mammalian cells. This new class of proteins is the foundation of Permeon Biologics' novel Intraphilin™ Technology Platform and provides an innovative approach to develop intracellular protein biologic drugs, such as intracellular monoclonal antibodies and enzyme replacement therapies. Intraphilins enable functional proteins to act inside cells to treat disease, impacting over 1,500 intracellular target proteins currently considered undruggable with available technologies.

The data were published online today in the journal Chemistry & Biology in a seminal paper by David R. Liu, Ph.D., professor of chemistry and chemical biology at Harvard University and investigator at the Howard Hughes Medical Institute, and his colleagues. The findings represent natural scaffolds for developing potent human intracellular biologic drugs, and also raise the possibility that some of these supercharged proteins may penetrate cells as part of their native biological functions. The ability of human Intraphilins to penetrate cells to enable intracellular protein biologics has not been previously reported.

"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 Dr. Liu, Permeon's scientific founder and scientific advisory board chairman. "Intraphilins are now being developed as a new class of human protein therapeutics to access previously undruggable intracellular target proteins and pathways."

The study sought to determine if this class of proteins could provide a natural platform for intracellular protein biologics in vivo. Dr. Liu and his colleagues tested the ability of Intraphilins to enable active enzymes in adult mice to function in cells of three tissues of therapeutic interest – the retina, pancreas and white adipose tissues. Intraphilins were fused to Cre recombinase, an enzyme that mediates DNA splicing inside the nuclei of cells, then injected into the mice.

Following a post-injection incubation period, each Intraphilin-Cre recombinase fusion protein tested exhibited DNA splicing activity in the nuclei of living cells in each of the tissues tested. These study results collectively establish that Intraphilins enable protein biologics to function inside a variety of living mammalian tissues in vivo. The paper shows that Intraphilin-Cre-injected retinae exhibited large areas of recombined cells in the eyes of treated mice. In contrast, retinae injected with Cre recombinase protein by itself did not show activity in vivo, highlighting that protein biologics are typically unable to enter cells. Of importance, the Intraphilins tested were able to mediate internalization of fused proteins with up to 40-fold higher potency than cell penetrating peptides, which have been used previously to develop intracellular biologics.

"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 Alex Franzusoff, Ph.D., president and board director of Permeon Biologics. "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. This paper shows for the first time that we can leverage natural human proteins to enable intracellular protein biologics, such as humanized intracellular monoclonal antibodies, to address clinically important targets of interest which were previously undruggable."

INFORMATION:

The Chemistry & Biology paper titled "A Class of Human Proteins that Deliver Functional Proteins into Mammalian Cells In Vitro and In Vivo" was published today online at http://www.cell.com/chemistry-biology and will appear in the July 29 print edition of the journal.

About Intraphilin™ Proteins

Many of today's blockbuster drugs are protein-based biologics that work outside of cells by binding to extracellular targets to treat disease. The size and electrical charge of these protein biologics normally would prevent them from penetrating cell membranes to gain access to intracellular targets, limiting the therapeutic utility of this class of drugs. Permeon Biologics' Intraphilin™ Technology Platform fuses therapeutic proteins to Intraphilins so that they can penetrate into cells by uniquely stimulating the natural pathway for cell uptake by endocytosis. Intraphilins have the potential to enable human biologic drugs – monoclonal antibodies, enzymes and transcription factors – to function inside of cells and treat disease.

About Permeon Biologics

Permeon Biologics is pioneering a breakthrough class of intracellular biologics that target a broad spectrum of previously undruggable targets. Leveraging its novel Intraphilin™ Technology Platform, which has been exclusively licensed from Harvard University, the company's next-generation approach is being developed to unlock the full therapeutic potential of current blockbuster technologies for human biologics, such as monoclonal antibodies, enzymes and DNA/RNAi-based therapeutics. Intraphilins are supercharged proteins that enable protein biologics to act inside cells to treat disease. This opens up access to more than 1,500 intracellular targets that are deemed undruggable by existing technologies. Based in Cambridge, Mass., Permeon Biologics is backed by marquee investors, ARCH Ventures and Flagship Ventures, and is led by a world-class scientific advisory board and proven management team. For more information, visit www.permeonbio.com.

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