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Pictured: An antibody-drug conjugate with a graduation cap over a soft background/Nicole Bean for BioSpace Pharmaceutical companies are clamoring to add antibody-drug conjugates to their portfolios as the number of clinical trials explodes and the next generation rises. Antibody-drug conjugates (ADCs) are biotherapeutics comprised of a monoclonal antibody designed to recognize an antigen on a target cell, a potent cytotoxic payload that triggers cell death and a linker binding the antibody and payload together. They are developed and used to treat various cancer indications. “ADCs are a better chemotherapy,” said Joe Catanzaro, senior biotech analyst at Piper Sandler & Co. “There will always be efforts to move away from chemotherapy, and if you can replace chemotherapy, that obviously opens up a multitude of opportunities.” Chemotherapy is notorious for causing deleterious side effects due to its lack of specificity. ADCs are effectively targeted chemotherapy, delivering cancer-killing material directly to malignant cells. Jake Van Naarden, president of Loxo Oncology at Eli Lilly, which recently acquired ADC player Mablink Biosciences, said the rampant success of AstraZeneca and Daiichi Sankyo’s Enhertu could be driving the uptick in ADC interest because the industry wants to replicate those results. He likened it to the race to find PD-1 inhibitors that can repeat the success of Merck’s Keytruda. Nathan Tumey Nathan Tumey, associate professor at the School of Pharmacy and Pharmaceutical Sciences at Binghamton University, concurred, saying, “The clinical success of this product breathed life into the ADC field in a way that I haven’t seen in many years.” In 2022, 57 ADCs entered Phase I clinical trials, a 90% increase over 2021, as reported by Clinical Leader. Researchers estimate that over 100 ADCs are being investigated across the spectrum of tumor types in various stages of clinical development. An Evolving Science ADCs are not a new technology. The first clinical trials involving an ADC were underway in the 1980s, with the first approval, for Pfizer’s Mylotarg (gemtuzumab ozogamicin) in acute myeloid leukemia (AML), coming in 2000. Mylotarg was subsequently withdrawn from the market after confirmatory trials failed to show benefit and raised safety concerns. A lower dose of the drug, with a different dosing schedule, was greenlit in 2017 for CD33-positive AML. What differentiates next-generation ADCs from those currently on the market, Tumey said, is the incorporation of novel features including site-specific conjugation, new payload mechanisms and new antibody formats. “These features are usually designed to expand the therapeutic window or push into new therapeutic indications,” he said. Sung Joo Lee, CEO of Orum Therapeutics, pointed to the success of Enhertu as a driver of next-gen ADCs. “Enhertu is basically an old antibody with an old linker with a different payload,” Lee told BioSpace. “That [payload] made a huge difference.” First approved in 2019, Enhertu is indicated for breast, non-small cell lung and gastric cancers. In a comparison between Enhertu and Kadcyla—an older generation ADC—published on Enhertu’s website, nearly 83% of HER2+ breast cancer patients treated with Astra and Daiichi Sankyo’s drug saw their tumors shrink compared to 36% of those treated with Kadcyla. Experts caution that there are challenges with ADCs that still need to be overcome, including toxicities and the tumor microenvironment itself. Tumey said there are still a lot of questions about what drives ADC toxicity. Previously, it was believed that the main driver was premature payload release, but he said this is no longer considered the main or only issue. “Even very, very stable ADCs have toxicity problems,” Tumey said. “Developing an understanding of the molecular basis for ADC toxicity would be a major step forward.” Catanzaro added that another challenge is the limited number of tumor-specific antigens in solid tumors. Joe Catanzaro Class of the 2020s France-based Mablink is using its PSARLink platform to improve the delivery of ADCs. Mablink’s science is based on the foundation that the hydrophobicity of the cytotoxic drugs used in ADCs degrades the pharmacological properties of the antibody when bound to it. This can cause systemic toxicity or damage to healthy cells and tissues in the body and premature release of the payload before the ADC encounters the cells it is designed to target. “Mablink has come up with a clever way to shield or protect the payload when it’s conjugated to the antibody,” Kristin Bedard, vice president of biologics at Loxo Oncology, told BioSpace. MBK-103, Mablink’s lead asset, targets folate receptor alpha, an overexpressed protein found in many solid tumors, including ovarian and non-small cell lung cancers. In animal studies, MBK-103 demonstrated anti-tumor activity in colorectal and ovarian cancer models. Orum is taking a different approach with ORM-6151, an anti-CD33 antibody-enabled GSPT1 degrader being developed to treat AML and patients with high-risk myelodysplastic syndromes. BMS paid $100M upfront for the novel ADC earlier this month. “We decided to work on GSPT1 because it’s a great target for AML,” Lee said. “Unlike toxins, GSPT1 degraders are very good at killing AML cells, but not good at killing hematopoietic stem cells.” Jake Van Naarden Orum presented preclinical data for ORM-6151 at the American Association for Cancer Research’s annual meeting in April demonstrating robust in vitro activity in AML models across a variety of clinical features and desirable pharmacologic properties. The FDA has granted approval for Phase I clinical trials to begin. Van Naarden said the primary question before the field is: Is Enhertu an outlier, or can it be replicated? “I think we don’t know,” he said. “The degree to which I think any one company is willing to sort of back the truck up in ‘ADC Land’ in some ways is a reflection of their conviction” that its success can be repeated. The general consensus among the experts interviewed by BioSpace is that the future of this space looks bright and full of innovation. “ADCs before were like black and white,” Lee said. “Now, it’s the era of color TV.” Hayley Shasteen is a freelance science writer based in Northeastern Ohio. You can reach her at hayleyshasteen@gmail.com or follow her on LinkedIn.

Eli Lilly's Jacob Van Naarden likens the antibody-drug conjugate frenzy to what happened in immunotherapy, with major companies chasing PD-1s. Editor’s note: From the moment Merck & Co. announced a multibillion-dollar deal with Daiichi Sankyo on the first day of the European Society of Medical Oncology Congress, antibody-drug conjugates emerged as one of the major biotech headlines from the conference. Here, we present the ESMO ADC Files, with more on the ADC frenzy. MADRID—Eli Lilly’s Jacob Van Naarden thinks his peers’ rush to snap up every antibody-drug conjugate (ADC) out there may be a little overblown. “We as a field have a tendency to sort of see shiny new objects and then assume there's going to be a zillion more shiny new objects in the same class. And I actually think historically, that's not been true,” Van Naarden told Fierce Biotech on the sidelines of the European Society for Medical Oncology (EMSO) Congress in Madrid. Van Naarden, who is president of Loxo@Lilly, likens the ADC frenzy to what happened in immunotherapy, with major companies chasing PD-1s. That breakthrough—led by Merck & Co.’s Keytruda and Bristol Myers Squibb’s Opdivo—revolutionized cancer care, no doubt, says Van Naarden. He just thinks the industry should have been more particular about the candidates. Instead, biopharmas went all in trying to pick up every last PD-1 in development. “Industry spent, what, tens of billions, maybe hundreds of billions of dollars, on immunotherapy to find the next PD-1, and that's largely not been a successful effort,” Van Naarden said. “So I think that we need to be careful as a field anointing classes of therapy instead of singular products or singular targets.” Industry spent, what, tens of billions, maybe hundreds of billions of dollars, on immunotherapy to find the next PD-1 and that's largely not been a successful effort." — Jacob Van Naarden At a conference where pharmas are jockeying for attention with flashing booths advertising their medicines, Van Naarden allowed that Enhertu, AstraZeneca and Daiichi Sankyo’s breast cancer and lung cancer med, “is amazing.” Astellas and Seagen also presented what he called a “transformative advance” for patients with bladder cancer for their ADC Padcev at ESMO. But not all the data have been great in this class. “There's other examples, actually, even at this meeting, of ADCs in registrational, phase 3 studies that I think are not that exciting, honestly,” Van Naarden said—withholding the names of those companies and drugs. Lilly, he says, prefers to be modality-agnostic, picking and choosing the therapies that will have the biggest impact for patients. “Across our entire portfolio, we take a very product-driven view of the world. In other words, do we like what this particular drug has the potential to do for these particular patients, almost regardless of the modality, and if we do then either we'll try and build one or we'll try and buy one if we could find what we like—versus, we believe in some whole new class that we're going to back up the truck on,” Van Naarden said. “The theme for us is: I want the ability to be able to make medicines in all of these different classes,” he continued. “That's different than to say that the next wave of innovation is going to come entirely from one new thing. I don't really believe that to be true.” Having said all that, Lilly still bought ADC biotech Mablink Bioscience earlier this month. The Big Pharma also had a PD-1, Innovent Biologics’ Tyvyt, which was once billed as a potential low-cost choice in a multibillion-dollar class. But the FDA ultimately rejected it in nonsquamous non-small cell lung cancer and reprimanded the partners for using China-only pivotal data that compared the experimental therapy to an outdated regimen. What was it that made Van Naarden and co. back up at least a smaller truck to Mablink? The lead candidate is a folate-receptor-alpha-targeted ADC that uses a topoisomerase payload and a novel linker technology. He likens the therapy to ImmunoGen’s Elahere, which was approved for platinum-resistant ovarian cancer by the FDA in November, calling that move a “big advance for those patients.” But Van Naarden thinks Lilly can do better with Mablink’s MBK-103, which he believes has a better payload and a better linker. Lilly had previously worked with ImmunoGen through a deal struck in 2011 but ultimately cut the partnership seven years later. The two are working together once again through a $13 million upfront, $1.7 billion biobucks deal that was signed in February 2022. Mablink was also Lilly’s second ADC deal of the year, the first being the acquisition of Emergence Therapeutics in June. With so much competitive interest in ADCs, it’s easy to imagine that biotechs in the space were inundated with phone calls and meeting requests from pharmas all over the world. That’s where Lilly has to be careful, Van Naarden says. Everyone can see the same public data, so if something is good, the price goes way up. At the end of the bidding, will there still be value in the program? “Very little ends up being left to the imagination. If everyone sees the same thing, that means that more people are going to be running after it,” he says. “In other words, they're buying it for a fair price, versus getting value out of the deal.” “We haven’t done, really, any of that,” Van Naarden says. Instead, Lilly has looked earlier, taking risks, like with Mablink and Emergence, which have preclinical products that are not yet being tested in humans. “We can all sit around the table and disagree about whether or not we think it's going to work,” Van Naarden said. “That’s actually what creates value, because if I think it's going to work and you don't think it's going to work, that means that I'll show up at the bidding table, and you won't.”   “Our strategy is to go earlier and take more risk and recognize that we're going to be wrong a bunch of the time,” he adds. “But that's OK.”