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Investment

Lilly recruits Avidity Biosciences to develop antibody-oligonucleotide conjugates

Avidity’s technology will help the duo get RNA therapies to immune cells

by Ryan Cross
April 22, 2019

 

LN-oligo.jpg
Credit: Avidity Biosciences
Avidity's technology conjugates antibodies to RNA-modulating oligonucleotides.

In a sign that large drug companies’ interest in RNA therapies is growing, Eli Lilly and Company has struck a research collaboration with Avidity Biosciences to develop oligonucleotide-based therapies related to immunology.

Avidity, a start-up based in La Jolla, California, is developing antibody-oligonucleotide conjugates to help deliver oligonucleotides—short RNA or DNA molecules—to specific cells throughout the body, where they can modulate disease-related RNA.

So far, companies have only successfully delivered oligo therapies to liver cells by intravenous injection and to the central nervous system by direct injection into the spinal fluid. Avidity is hoping to expand oligos’ reach by attaching them to antibodies, which bind surface proteins on specific cells in the body. Once there, the oligos enter cells and can silence or modify the output of genes.

To get access to Avidity’s oligo-delivery technology, Lilly will pay Avidity $20 million up front and make a $15 million investment in the start-up. Avidity could also earn up to $405 million in development and commercial milestone payments for each target it drugs. Kent Hawryluk, Avidity’s chief business officer, says the collaboration includes “multiple targets in immunology and other disease areas.”

It’s the third RNA therapy collaboration Lilly has struck in two years. In 2017, the drug maker partnered with CureVac to begin developing messenger RNA–based cancer vaccines. And in 2018, it struck a deal that earned the RNA interference (RNAi) company Dicerna Pharmaceuticals $200 million to begin developing gene-silencing therapies for cardiometabolic diseases, pain, and neurodegeneration. In February, Lilly even installed a new chief scientific officer of RNA therapeutics to manage its growing portfolio of RNA programs.

“There is a huge surge of research in oligonucleotide therapeutics,” says Arthur Levin, Avidity’s executive vice president of R&D. That surge has been propelled by two success stories. The first is Biogen’s commercialization of a single-stranded antisense oligo drug called Spinraza. The second is Alnylam Pharmaceuticals’ launch last year of Onpattro, which was the first RNAi therapy ever approved.

Avidity’s technology can be used with any kind of oligonucleotide therapy, Levin says, including single-stranded antisense oligos and double-stranded RNAi. Avidity itself has preclinical programs using its antibodies to shuttle oligos to muscle cells to treat genetic diseases including myotonic dystrophy type 1 and Duchenne muscular dystrophy.

For those muscle disease therapies, Avidity is using an antibody that targets the transferrin receptor on the surface of muscle cells. Once there, the cells engulf the antibody-oligo conjugates into compartments called endosomes, where the antibodies are digested. The oligos are protected from the harsh environment with chemical modifications, Levin explains, allowing them to escape the endosome and do their gene-silencing or gene-altering jobs inside of cells.

Avidity plans to use these principles in its collaboration with Lilly to target proteins found in specific types of immune cells and other cells.

Other oligo companies are also hot on the trail of designing RNA-based therapies that target specific cells. Earlier this month, a start-up named Dyne Therapeutics launched with $50 million to develop antibody-oligo conjugates for genetic muscle diseases. Just days later, Regeneron Pharmaceuticals made a deal to pay Alnylam $800 million to develop RNAi therapies that target the eye and central nervous system.

Despite the recent surge in investment, the idea of targeted oligo therapies isn’t entirely new. In fact, Levin acknowledges that others have unsuccessfully tried to develop antibody-oligo conjugates in the past. Part of the trick for getting the conjugates to work this time is using the right linker molecule to connect the oligo to the antibody and finding the right place on the antibody to attach the linker. “We tried some things there were not obvious,” Levin says.

For now, Avidity is keeping the chemical details of the conjugates close to home, but it isn’t being shy about its ambitions. “With our technology we marry 30 years of monoclonal antibody experience with 30 years of oligonucleotide experience,” Levin says. “This deal really represents the maturation of oligonucleotide therapeutics.”

CORRECTION:

This story was updated on April 23, 2019, to correctly identify antisense oligos as single strands and RNAi as double strands.

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