Antibody-drug conjugates (ADCs) are making a comeback. After a relatively slow start with Adcetris (brentuximab vedotin, Seattle Genetics Inc.) and Kadcyla (ado-trastuzumab emtansine, Roche Holding AG) approved by the FDA in 2011 and 2013, respectively, the regulatory activity has swelled with four FDA approvals over the last nine months. (See Recent ADC approvals, below.)

"We're in a renaissance for the field," Peter Lamb, executive vice president, scientific strategy and chief scientific officer at Exelixis Inc., told BioWorld. "Folks have sorted out a number of the issues that have historically plagued ADCs and that is now being borne out in some pretty compelling clinical results."

With multiple moving parts – an antibody, a linker and a payload – it's been challenging to find the right combinations to create ADCs with good therapeutic indexes where a drug can be effective but not too toxic, which is especially important with the increasing use of combination therapies in oncology. "It's not a one size fits all. You can't just take the same linker warhead over and over again and put it on different antibodies," Lamb said. "Each one needs to be optimized as an individual program."

And the linker can be especially tricky because it must be stable in the bloodstream, but then it needs to be labile and release the drug once inside the cancer cell. "If you don't release the drug inside of the tumor cell, you don't really get activity because that drug is buried within that large macromolecule and it can't dock where it needs to," Clay Siegall, president, chairman and CEO of Seattle Genetics Inc., told BioWorld. The Bothell, Wash.-based company solved that problem by making its linker susceptible to cleavage by proteases in the cell.

And even with a good linker that's stable in the bloodstream, companies need to make sure the half-lives of the antibody and the drug are similar because if the antibody is being degraded faster, it will create a lot of free drug that can kill cells indiscriminately.

Business development ramps up

The ADC renaissance has caught the eye of the business development folks with multiple deals announced recently.

On Sept. 8, Exelixis, which has traditionally been a small-molecule drug company, announced two discovery deals for ADCs with NBE-Therapeutics and Catalent’s Redwood Bioscience subsidiary. The deals follow Exelixis' move into the ADC field last year through a discovery deal with Iconic Therapeutics Inc.

Peter Lamb, executive vice president, scientific strategy and chief scientific officer, Exelixis

"That deal [with Iconic] in many ways prompted us to look at the ADC space generally. We spent quite a while looking at what the status of the space was," Lamb said. "We felt there was a lot of interesting opportunities and technologies available to make next-generation ADCs that would improve upon what has been done historically and increase the chances of success."

In the deal with Basel, Switzerland-based NBE-Therapeutics, Exelixis gains access to NBE's SMAC-Technology for site-specific conjugation of the linker to the antibody. Older coupling technologies can create products that aren't homogenous and can aggregate, causing toxicity as they're trapped in the liver. The two-year discovery deal, which includes a $25 million up-front payment to NBE, gives Exelixis an option to license ADCs for an undisclosed number of targets. NBE is eligible for development and commercialization milestones, as well as royalties on net sales of products for which Exelixis exercises its option.

Redwood Biosciences, of Somerset, N.J., also has a site-specific bioconjugation technology, which it calls SMARTag. The three-year discovery deal allows Exelixis to use SMARTag to create ADCs for an undisclosed number of antibodies in Exelixis’ growing preclinical pipeline. Exelixis paid $10 million up front for the option and will make a decision about licensing the candidates prior to filling of an IND.

On Sept. 13, Gilead Sciences Inc. made a major move into the ADC space with its $21 billion acquisition of Morris Plains, N.J.-based Immunomedics Inc. Through the deal, Gilead gains access to Trodelvy, an ADC targeting trophoblast antigen2 (TROP2), which generated $20.1 million in revenue during the first two months on the market. Beyond the current approval for metastatic triple-negative breast cancer after at least two prior therapies for metastatic disease, Immunomedics is testing Trodelvy in a variety of TROP2-expressing tumors, including metastatic urothelial cancer and HR+/HER2-negative breast cancer.

A day later, Merck & Co. Inc. jumped into the ADC arena through a licensing deal for Seattle Genetics Inc.'s ladiratuzumab vedotin (LV), an ADC targeting LIV-1 being developed for breast cancer and other solid tumors.

Kenilworth, N.J.-based Merck is paying $600 million up front for half of the worldwide rights and agreed to invest $1 billion in Seattle Genetics through the purchase of stock at $200 per share. Seattle Genetics is also eligible for progress-dependent milestone payments of up to $2.6 billion.

Merck and Seattle Genetics will split the costs of development and profits for LV and other LIV-1-targeting ADCs. In addition to testing the drug as a monotherapy, the companies plan to test LV in combination with Merck's PD-1 antibody, Keytruda (pembrolizumab), in triple-negative breast cancer, hormone receptor-positive breast cancer and other LIV-1-expressing solid tumors.

Outside of ADCs, the duo also did a deal for Tukysa (tucatinib), Seattle Genetics' small-molecule tyrosine kinase inhibitor, which will give Merck a license to sell the drug in Asia, the Middle East and Latin America and other regions outside of the U.S., Canada and Europe. In the Tukysa-deal, Seattle Genetics will receive $125 million up front and is eligible for progress-dependent milestones of up to $65 million.

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