The antibody-drug conjugate (ADC) space has evolved significantly from its first-generation of products says Exelixis, which is increasing its presence in the sector through a pair of deals.

“Exelixis has a long history of success in small molecule drug discovery and development, rooted in an approach that focuses on understanding cancer biology and applying our expertise and technology to build therapies that address it,” Peter Lamb, chief scientific officer at Exelixis, told this publication.

Cabometyx (cabozantinib), Cometriq (cabozantinib), Cotelic (cobimetinib) and Minnebro (esaxerenone), have all reached commercialization, and now the firm is looking to emulate such success in the biologics space.

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“As we move into the biologics space, the modalities and mechanisms may be different, but our fundamental approach to the problems haven’t changed.”

Exelixis has chosen to focus specifically on ADCs. The modality – a highly potent small molecule payload linked to a targeting antibody – has been around for 20 years but only nine are commercially available, five of which being approved in the past 15 months.

“The antibody-drug conjugate space has evolved significantly, based on lessons learned from difficulties encountered in developing first-generation ADCs,” said Lamb. Problems in the early ADC space included immunogenicity issues related to the use of nonhuman antibodies, unstable linker technologies, and low bioactivity.

NBE deal

In the first deal, Exelixis is paying NBE-Therapeutics $25 million to develop ADCs using NBE’s conjugation and novel anthracycline-based payload platform.

“NBE has assembled a set of technology platforms that make it easier to discover, develop, and manufacture high-quality antibody-drug conjugates (ADCs),” Lamb told us.

“We were interested in partnering with them for two reasons primarily: their site-specific conjugation technology that makes it possible to attach a small molecule drug to a specific site on a monoclonal antibody, which has benefits for efficiently manufacturing homogenous ADCs; and their proprietary PNU anthracycline payload / linker platform, which has the potential for best-in-class serum stability while also maintaining high potency.”

According to Lamb, conventional ADCs, have “quite a few liabilities, including limited serum stability — increasing the likelihood that they degrade in plasma before they reach their intended target — and high degrees of heterogeneity, meaning they differ on an individual level with regard to the drug-to-antibody ratio and their functional properties. NBE’s site-specific conjugation technology, or SMAC-Technology, has the potential to address each of these limitations.”

SMARTag

In a separate deal, Exelixis is tapping up contract development and manufacturing organization (CDMO) Catalent for use of its Redwood Bioscience subsidiary’s SMARTag site-specific bioconjugation technology.

A $10 million upfront payment will see Exelixis receive an exclusive option to nominate up to a fixed number of targets using the ADC platform over a three-year period.

This demonstrates Exelixis’ “multi-pronged approach” to ADCs, Lamb said.

“The Catalent and NBE technologies are distinct but also complementary: entering into both collaborations gives us access to a wide variety of payloads, potentially allowing us to tailor ADCs to different tumor types based on their intrinsic sensitivities to payloads with differing MOAs.

“The deals announced this week also build on our prior biologics-focused agreements, including our exclusive option and license agreement with Iconic Therapeutics for ICON-2, a Tissue Factor-targeting ADC that we plan to file an IND for later this year. As we move beyond our small molecule medicinal chemistry roots into the biologics domain, we’re excited at the potential for each of these collaborations to yield product candidates that could one day become Exelixis medicines.”