4:34 PM
Jun 15, 2017
 |  BC Innovations  |  Tools & Techniques

Breaking the barrier

Companies are finally finding ways to develop cell-penetrating biologics

A three-way deal between Amgen Inc., Feldan Therapeutics Inc. and Elasmogen Ltd. is the latest cause for optimism that technologies are finally converging to enable the generation of cell-penetrating biologics.

The biotechs join a small but growing cohort of companies creating protein-based therapeutics that can cross the plasma membrane to reach intracellular targets - a challenge that has plagued the field almost since the dawn of the industry.

Last month, the partners signed a deal to combine Feldan’s intracellular delivery platform, dubbed Shuttle, with target-binding small proteins from Elasmogen, a 2016 spinout from the University of Aberdeen. Amgen is selecting two undisclosed targets. Financial terms have not been disclosed.

While small molecules can easily penetrate cell membranes to hit intracellular targets, they require a defined, hydrophobic binding pocket, leaving many intracellular targets undruggable. Small molecules also often lack specificity, in particular when multiple targets have similar binding pockets.

Antibodies can solve the specificity problem, but because they cannot cross the lipid bilayer they have been largely restricted to extracellular targets.

“The goal for years has been to develop a method combining the targeting power of biologics with the cell penetrating abilities of small molecules,” said Heehyoung Lee, senior director of target discovery and validation of LA Cell at Sorrento Therapeutics Inc. LA Cell is a 2015 JV formed between Sorrento and City of Hope to develop antibodies and peptides against intracellular targets.

Now, activity in the field is showing a palpable rise. Patents on cell-penetrating peptides or antibodies increased in the last decade, and rose sharply in the last three years, with about twice the number published in 2014 over 2013 (see “Patents on Cell-penetrating Biologics”).

Figure: patents on cell-penetrating biologics

The number of published patents involving cell-penetrating peptides surged in the last three years, more than doubling from 47 in 2013 to 102 in 2014. The increase in IP activity parallels a growing commercial interest in the technology in recent years. The chart includes all worldwide issued patents and patent applications published since 2000 that contain the words “cell-penetrating peptide,” “cell-penetrating antibody,” “cell-permeable peptide,” “cell-permeable antibody,” “cell-permeating peptide,” or “cell-permeating antibody” in the patent’s English-language abstract. Source: World Intellectual Property Organization Patentscope database

Last year, Merck & Co. Inc. became the first pharma to disclose a play in the field, partnering with Complix N.V. to use the biotech’s Alphabody platform for reaching intracellular targets, and Orum Therapeutics Inc. was launched to use a cell-penetrating antibody technology from Ajou University for creating cancer therapeutics. Yesterday, Orum raised $8 million in a series A round.

In addition, Harvard University professor Greg Verdine has formed two companies to commercialize cell-penetrating stapled peptide technology from his lab. Earlier this month the first, Aileron Therapeutics Inc., proposed to raise $69 million in an IPO on NASDAQ. The second, FOG Pharmaceuticals Inc., was launched in 2015 to develop a next-generation form of the stapled peptides.

“Biologicals for intracellular targets are experiencing an emerging wave of interest, which happens in this business at certain moments when all of the critical parameters have been addressed. We saw this happen when everything came together for antibodies in the 1990s, then RNAi emerged as a new class. I think biologicals for intracellular targets will be one of those new fields,” said Complix CEO Mark Vaeck.

Sorrento EVP of Corporate Development Miranda Toledano told BioCentury the problems have been in achieving therapeutically relevant quantities for the intracellular targets.

“There have been a number of historical attempts,” she said. “Earlier technologies, such as...

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