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Alnylam Widens Stable of Delivery Partners with Molecular Templates Collaboration

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By Bernadette Toner

Marking its second delivery collaboration in as many months, Alnylam has forged an alliance with biopharmaceutical firm Molecular Templates to explore the potential of the company's biologics for targeted delivery of RNAi therapies.

The agreement, announced last week, follows a deal that Alnylam signed in late April with Precision Nanosystems to discover and develop novel small lipid nanoparticles using microfluidics (GSN 4/21/2011). It also comes amid an ongoing lawsuit between Alnylam and partner Tekmira Pharmaceuticals over rights to Tekmira's LNP technologies that Alnylam has been using in some of its drug candidates.

Molecular Templates, based in Georgetown, Texas, is developing molecules called Engineered Toxin Bodies, or ETBs, which are derived from bacterial toxins that have been engineered with a unique targeting domain and designed for reduced immunogenicity, while retaining the biological properties of the parent scaffold.

Specifically, the ETBs are based upon the A subunit of the protein shiga-like toxin 1. The subunit lacks binding affinity but induces internalization, endosomal escape, retrograde transport to the cytosol, and ribosomal inhibition. The company introduces targeting domains into an engineered SLT1A scaffold to confer selective binding activity while preserving the desirable therapeutic properties of the scaffold. In addition, it removes and alters regions of the molecule that are predicted to be promiscuous high-affinity MHC class II sites in order to reduce the immunogenicity of the ETBs.

The company claims that ETBs are able to home in on cell surface or intracellular targets that are problematic for antibody and small molecule approaches — a feature that makes them suitable for therapeutics in their own right, as well as for delivery of payloads such as siRNAs.

The company is developing ETB therapeutics across a wide range of disease areas, including cancer, autoimmune, and infectious disease, but views delivery as "one way to leverage our platform," CFO Jason Kim told Gene Silencing News. "Not only can we develop these standalone therapeutics on the back of what we believe is a pretty differentiated mechanism of action in cancer, but we can also, because of the unique capabilities of these ETBs, add [other] mechanisms of action, like delivering payloads."

Kim said that siRNAs are only "one type of payload" that the ETBs can deliver. He noted that the company is currently evaluating other possibilities but declined to elaborate.

Alnylam is Molecular Templates' first RNAi partner. "The RNAi space is a very interesting space for us," Kim said. "Clearly, there have been a lot of tectonic shifts in the area, but with a partner like Alnylam we feel very comfortable working on and developing ETBs to deliver siRNAs with them."

The companies did not disclose financial details or other terms of the partnership.

Kim said that ETBs have several advantages for RNAi delivery. "Not only can they be directed to a specific target to then internalize into the cell, but they can also self-route themselves to the cytosol. That's where you want to be if you're developing something like a siRNA."

He added that the active intracellular properties of the ETBs "make them unique among some of the other delivery technologies out there."

Because their primary mechanism of action is ribosome shutdown, "in order for them to impart their mechanism of action, typically, they need to be able to route themselves with the cell and get to where they need to go," Kim said. "That's a key feature of the technology that we're trying to leverage in delivering siRNAs."

He added that the company aims to address the "key challenge" in RNAi delivery, which is delivering siRNAs in a more targeted manner. "Obviously, that includes being able to go after targets that are not localized in the lungs or liver, which is where you see a lot of these other delivery technologies applied," he said. "We're trying to deliver siRNAs outside of those areas."

The company has not published any papers on its RNAi work but did present a poster at the RNAi and miRNA World Congress in Boston in late April. In the poster, company researchers described how they conjugated siRNA specific to GAPDH to an ETB that included a mutation intended to disrupt the molecule's innate ribosomal inactivating activity. The ETB-siRNA conjugate exhibited cell-specific siRNA delivery in a melanoma cell line, with "substantial gene knockdown" at siRNA concentrations as low as 100 pM, according to the poster.


Have topics you'd like to see covered in Gene Silencing News? Contact the editor at btoner [at] genomeweb [.] com.

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