The next wave in ADCs

How next-gen ADCs aim to improve homogeneity, go beyond cancer

After about 25 years of development, antibody-drug conjugates have gained acceptance as a validated approach to the targeted killing of cells, with two drugs approved in the past two years. While Seattle Genetics Inc. and ImmunoGen Inc. have owned the space, a variety of biotechs are developing next-generation ADCs that seek to improve the technology and broaden its scope beyond cancer to inflammation and autoimmune diseases.

These advances include producing a more homogeneous drug product and delivering more potent payloads that move beyond the delivery of blunt, cytotoxic agents. Other approaches include developing ADCs as a delivery system for targeted small molecules.

Further down the line companies are beginning to think outside the box, which now is defined as "antibody linked to a payload." A mAb that has cytotoxic amino acids built into its sequence exemplifies such new thinking.

The combination of product approvals and new approaches has increased investor interest in the field. Indeed, Seattle Genetics' stock is up 145% since the beginning of 2012, while ImmunoGen is up 40%.

In 2012, four next-generation ADC companies raised more than $150 million in venture funding.

None of these companies have raised money so far in 2013, but last week Bind Therapeutics Inc. filed to raise up to $80.5 million in an IPO underwritten by Credit Suisse; Cowen; Stifel; and JMP Securities.

What these next-generation technologies need is clinical data that can validate the platforms and attract big industry players. Most of those are at least a year or two away, as there are no molecules in the clinic from next-generation ADC companies except for Bind's Accurins, which employ a nanoparticle with targeting ligands.

ADCs: Take One

Seattle Genetics and ImmunoGen developed similar technologies that have been widely out-licensed.

Both technologies use naturally occurring amino acids in the antibody as anchor points for attaching a cytotoxic drug. Seattle Genetics' technology uses cysteine, whereas ImmunoGen's Targeted Antibody Payload (TAP) platform uses lysine.

The technologies use different cytotoxic payloads, although both are microtubule-disrupting agents. Seattle Genetics employs auristatins like monomethyl auristatin E (MMAE), while ImmunoGen uses maytansine derivatives like DM1.

Both have engineered linkers that aim to keep the cytotoxic agents welded to the mAbs until the ADC reaches the cancer cell. Once internalized, the linker is cleaved, releasing the cytotoxic agent to kill

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