abc of eet, page-2

Hi Wayne -

I find it interesting regarding no comment from you in relation to Arrowheads DPC delivery system and its ability for Endosomal Escape after putting it forward in the last thread but simply met with a reply referring back to the session title at this years event ?

ARWR presented last year also at the same event as PYC - again they are at TIDES this year with a few presentations the first day being probably the most directed piece from them regarding EET - Unpublished Data Using Endosomal Escape Agents for siRNA Delivery in vivo David L. Lewis, Ph.D., Chief Scientific Officer, Arrowhead Research Corporation.

While yes ARWR being focussed on siRNA in line with their own drugs I don't see why DPC technology cannot be applied across delivery of other biologics in much the same way.

I'll re-paste these posts here but there is plenty of information out there for further research.











Here's a little bit on ARWR and a guess a vote of confidence in that they travel the same path for endosmal escape and siRNA back to pathogens -


The DPC delivery system represents an elegant solution to the siRNA delivery problem, specifically designed to overcome barriers to systemic administration of siRNA. First developed by our scientists in Madison, Wisconsin, the inspiration for DPC technology came from the physical characteristics of viruses, nature's own nanoparticles for nucleic acid delivery.

Viruses are efficient at finding their target cells and delivering their nucleic acid payload to the proper cellular compartment. Key features of viruses are their small size, their overall negative surface charge, their specificity for particular cell types based on receptors unique to that cell, and their ability to disassemble and release their nucleic acid cargo to the proper cell compartment in response to cellular triggers. All of these features are incorporated into DPC technology.

DPCs are small nanoparticles, 5-20 nanometers (nm) in size, composed of an amphipathic polymer to which shielding agents such as polyethylene glycol, as well as targeting ligands are reversibly attached. In some constructs, the siRNA payload is attached to the DPC, while in other constructs, the siRNA circulates attached to a different carrier. When attached, the DPC construct protects the siRNA payload while allowing the polymer to circulate in the blood without creating undue toxicity.

The targeting ligand guides the nanoparticles to the cell of interest where, together with the siRNA, it is taken up into a membrane-enclosed cellular compartment known as an endosome. The polymer is selected for its ability to lyse the endosomal membrane which releases the siRNA into the cytoplasm. There, it engages the cell's RNAi machinery, ultimately resulting in knockdown of target gene expression.

The lytic chemistry of the DPC polymeric backbone is modified, or "masked", using proprietary chemistry. Masking of the polymer's lytic chemistry accomplishes two interrelated objectives that are critical to in vivo siRNA delivery:

•Reduction of toxicity by controlling when the membrane lytic property of the polymer is activated.

•Inhibition of non-specific interactions with blood components and non-targeted cell types.

Link HERE




and here for Homing Peptides & PDC


"Arrowhead's Homing Peptides™ comprise the world's largest library of human-derived peptide sequences that have been shown to localize to specific tissues in the human body. This platform enables the creation of "guided therapeutics" that specifically target tissues of interest while sparing off-target issues. The vast and growing proprietary library of Homing Peptides™ and numerous novel cell surface targets provide Arrowhead with building blocks for its own internal pipeline of drug candidates as well as opportunities to out-license or collaborate with partners. Our identification and screening techniques have discovered peptide sequences that target known receptors, as well as novel, tissue specific receptors. Importantly, the platform enriches for receptors that rapidly internalize the sequence and its associated payload.

To date, with partner MD Anderson Cancer Center, drug candidates targeting cancer and obesity have been developed using sequences discovered by this method. These candidates are "peptide drug conjugates" or "PDCs" which link the homing sequence to a potent toxin that induces cell death. This approach has the potential to yield numerous other PDC candidates for targeting nearly every tissue in the body for a wide variety of indications. Other areas of development may include monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), and diagnostics.

Peptide Drug Conjugates

Peptide-drug conjugates (PDCs) are structurally simple and include a peptide that selectively targets certain cells, a potent cell killing drug molecule, and linker chemistry which can be tuned so the conjugate exhibits the desired pharmacologic properties. PDCs share the promise of antibody-drug conjugates (ADCs), but can be faster and simpler to develop. As evidenced by clinical data from other developers, guided therapeutics such as ADCs and PDCs are a promising new frontier in cancer treatment because they hunt and destroy primary and metastatic cancer cells with potentially greater safety margin.

Several PDCs yielded by Arrowhead's platform are currently under clinical and preclinical investigation. Adipotide™, which targets Prohibitin, a receptor found exclusively on adipose (fat) tissue, is enrolling patients in a Phase 1 clinical study at MD Anderson Cancer Center in Houston, TX.

BMTP-11, targeting the IL 11R receptor, has provided clinical proof of concept for the using of Homing Peptides™ in cancer treatment. Results from a Phase 1 study in metastatic prostate cancer patients have been submitted for publication.

Link HERE


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