3:13 PM
Jan 25, 2018
 |  BC Innovations  |  Strategy

Takeda rides Denali’s ATV

Denali deal reflects Takeda’s growing commitment to biologics for CNS disorders

Editor's Note: This article was updated on Jan 29, 2018 at 11:29 AM PST

In its deal with Denali, Takeda has not only boosted its CNS pipeline, but also gained access to a delivery technology that could open the door to a host of CNS targets only druggable with biologics. As the pharma continues to ramp up the therapeutic area, the Denali system could provide a gateway technology for other assets acquired or grown in house.

Since the arrival of CSO and CMO Andrew Plump in 2015, Takeda Pharmaceutical Co. Ltd. has been increasingly looking externally for modalities that can complement its expertise in small molecules.

Plump told BioCentury in a conversation in June that among the pharma’s three core therapeutic areas -- CNS, cancer and gastrointestinal disorders -- “the one that is most challenging to diversify from on a modality basis is CNS, because it’s just hard to get into the brain.”

The technology from Denali Therapeutics Inc. offered a way for the pharma to unlock a trove of neurology targets, according to Daniel Curran, head of Takeda’s Center for External Innovation. “Recently some targets have emerged that require biologics to inhibit or activate,” said Curran.

“We could build abilities in-house, but that would take too long. We went into the Denali deal explicitly to try and understand this ATV transport system,” he added.

Denali’s ATV (antibody transport vehicle) system puts a new spin on the “Trojan horse” strategy that Denali CEO Ryan Watts helped develop when he was director of neuroscience at the Genentech Inc. unit of Roche.

Both systems target the transferrin receptor on the luminal surfaces of vascular endothelial cells. Receptor binding triggers endocytosis, causing the receptor and its cargo to traffic across the cytoplasm to the opposite (basolateral) surface, where the cargo undergoes exocytosis into the CNS, co-opting the natural route by which transferrin carries iron into the brain (see “Crossing the BBB”).

Figure: Crossing the BBB

Takeda Pharmaceutical Co. Ltd. (Tokyo:4502) and Denali Therapeutics Inc. (NASDAQ:DNLI) signed a deal this month to use Denali’s antibody transport vehicle (ATV) technology to develop three antibody products for neurodegenerative disease. The ATV technology, which Denali developed in collaboration with F-Star Biotechnology Ltd., involves engineering therapeutic antibodies that cross the blood-brain barrier (BBB) by binding transferrin receptor (TFRC; TFR; CD71).

Left panel: The platform’s core antibody (gray) has three antigen-binding sites: two arms that can bind a single target with high avidity or bind two different targets like a standard bispecific antibody; and an Fc region engineered with a binding site (orange) for transferrin receptor (TfR), which is expressed on the brain endothelial cell membranes that form the BBB.

Right panel: After an ATV in the blood binds TfR on the BBB, it is endocytosed and transported across the endothelial cell in endosomal vesicles (brown circles), then released into the brain, where the two other ATV arms can bind therapeutic targets. ATV binding of TfR does not disrupt normal iron metabolism because it does not compete with transferrin (dark blue hexagon) for TfR binding. In contrast to some other BBB-traversing strategies, ATV does not disrupt gap junctions between endothelial cells (green), leaving normal...

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