As the former head of cell and gene therapy at Novartis Oncology in Europe and the person responsible for launching the first-ever commercial CAR-T, it’s probably not an overreach to say that Emanuele Ostuni, PhD, has extensive knowledge about cancer treatment. He also has an insatiable appetite for challenging himself to find novel solutions for complex problems. Ostuni departed Novartis in early 2022 to take the helm of the covert start-up ARTBIO after developing a keen interest in the burgeoning field of radioligand therapy (RLT).
It was a bold move, considering how packed and fast-paced the RLT industry was already, despite its infancy. Not only were next-gen companies like RayzeBio emerging when Ostuni joined ARTBIO, but major pharmaceutical companies like Bayer had already acquired programs like XOFIGO (radium Ra 223 dichloride) and Novartis had acquired Endocyte, leading to the RLT Pluvicto that had been approved by the FDA. And yet, Ostuni believed that ARTBIO’s new class of alpha radioligand therapies (ARTs) had the potential to be the safest and most effective drug currently available.
“Although the mechanism and chemistry are complex, RLTs are relatively easy to understand,” Ostuni told Inside Precision Medicine. “The radioligand strategy simply elevates next-generation precision oncology by utilizing radiation.”
Since then, the company has quickly elevated itself to a major player in the field of radioligand therapy, launching in 2023 with $23 million in seed funding and then, just six months later, collecting $90 million for a Series A. In today’s dicey financial environment, that isn’t chump change, and now, they’ve got even more.
The now clinical-stage radiopharmaceutical company announced the closing of a $132 million Series B financing co-led by new investors Sofinnova Investments and B Capital, along with a life sciences-dedicated investment fund that invested previously. Further support came from existing investors F-Prime, Omega Funds, and Third Rock Ventures, and new investors Qatar Investment Authority and Alexandria Venture Investments. The company will use these proceeds to advance its novel alpha radioligand therapies (ARTs), an approach that has three core pillars: research and development, manufacturing, and supply chain.
“It has not been an easy time to be fundraising, and it was critical to have [investor] support so that we can move forward with execution and be more free to focus on what is most important: getting data, getting drugs to patients, and demonstrating that everything is working properly,” Ostuni said. “We’re here to build better products for patients. We’re here to build better centers of care.”
The yin-and-yang of RLTs
When considering oncology today and throughout history, there have been three main approaches: surgically removing the tumor, using chemotherapy to destroy it, or applying external beam radiation. The next generation of oncology has been based around targeting cancers with “molecularized” chemotherapy and radiation.
A lot of this precision oncology wave has been driven by antibody-drug conjugates (ADCs) that deliver chemotherapeutic agents directly to tumor cells by using antibodies as carriers. Radioligands work in a similar way by using antibodies, small molecules, or peptides to specifically target the tumor and deliver radiation right to it, which reduces the impact on the rest of the body. ARTBIO and others have opted for the small-molecule and peptide approach.
“We typically do not work on antibodies because they are too long-lived,” said Ostuni. “They spend too much time in the bone marrow, which is the most radiation-sensitive organ that we have. Much of the radiotherapy industry has transitioned from using antibodies to employing small molecular weight agents, such as peptides and small molecules, which tend to have a relatively short lifespan within tumors.”
The choice of ligand goes hand in hand with the selection of a tumor target, ideally one that is expressed in cancer cells only. The other half of the puzzle is finding the right radioisotope, the main choices being the powerful, short-range, and longer-lived alpha emitters and the weaker, longer-range, and shorter-lived beta emitters. According to Ostuni, the radioisotope therapy industry first went with alpha-emitters, which have a 9.9-day half-life. Though the higher-powered alpha emitters have a more definitive ability to kill tumor cells, these radioisotopes typically remain in tumors for no more than two to three days.
To Ostuni, that’s a far from optimal approach. “We believed that if we used those types of molecules and paired a two-to-three-day ligand for the tumor with a 9.9-day radiation payload, we would be missing out on a significant amount of radiation that the payload could emit at the tumor site.”
To prioritize delivering the most radiation safely into tumors, maximizing efficacy and improving safety, Ostuni and ARTBIO have honed in on their version of an alpha-emitting radioisotope: clinical-grade lead-212 (212Pb), which has a significantly shorter half-life than actinium, at around 10.64 hours. There have been two approvals to date for radioisotope therapies that emit beta particles. Lutathera (Lutetium Lu 177 dotatate) is approved to treat neuroendocrine tumors that start in the pancreas or digestive system. The other one is Pluvicto (Lutetium Lu 177 vipivotide tetraxetan), which is approved for adult patients with prostate cancer that has spread and is resistant to hormone therapy and taxane-based chemotherapy.
To add to the complexity, the RLT approach isn’t a simple plug-and-play—you can’t just pair your radioisotope of choice to your ligand of choice and expect the conjugated molecule to work the way each of those components does in isolation. Rather, every program has to be very much customized, which isn’t just an issue with RLTs; ADCs also necessitate optimization tailored to the particular tumor, its environment, and its chemistry.
“The RLT chemistry is not like Legos,” said Ostsuni. “The biology of the target has to be really exquisite and well understood. Then you’ve got to get the chemistry right and really work through to make sure that that combo really works. You can’t take this molecule, throw this isotope on it, and call it a day. We’ve tried that, and it doesn’t work. You have to optimize many other things around the properties of the molecule.”
Science as an ART (and business)
ARTBIO hasn’t released too much information on their RLT R&D process, with Ostuni only disclosing that the process involves x-ray structures and docking models. For Ostuni, the in silico approach can aid in drug design; it’s useless if it doesn’t work in humans. “At some point, you have to do the experiment because we’ve cured a lot of mice, but we haven’t achieved the same with adults or children, for that matter, so we really have to always go back to the labs and get the work done,” said Ostuni. “There’s a lot of new tech that we’re deploying that allows us to get the assessments faster and also look at how the data from animals translates to humans.”
Once ARTBIO has its ideal radioisotope candidates in hand, a whole new set of challenges arises: supply chain and manufacturing. “What we found as we built the company was that, although the mechanism by which we kill cells is simple, the mechanism by which we would make the drug product and we would deliver it to patients is actually quite hard,” said Ostuni. “As John Babich, PhD, director, president, and chief scientific officer of Ratio Therapeutics, likes to say, ‘We have to ship ice cream without an icebox, right, and it’s got to get there on time to be eaten.’”
To produce lead, ARTBIO has developed a proprietary technology called AlphaDirect, which has been used to make clinical doses daily that are deployed into a distributed manufacturing network to supply our trials. Ostuni said that ARTBIO is in the process of establishing the supply chain in the U.S. and Europe to serve as a true demonstration of an effective supply chain, rather than merely attempting to operate in one city and transport doses locally.
Ostuni does not want to have ARTBIO land in a situation where the rate-limiting factor is supply chain or manufacturing, and that’s where this Series B funding really comes in. “Our manufacturing is sufficient for the clinical stage, but we’re already thinking about how to scale it for the next level of capacity inflection. This round primarily focuses on establishing the core initial supply chain and transitioning the key first program into phases I and II, while also moving the second program into phase I. This approach allows us to have two additional programs in development, ready to mature for the next transition. It’s a big step for us as a company, an inflection point in terms of what we will look like in 18 months.”
If ARTBIO can’t do all three of these things, the company will fall short of its value proposition. “If you have phenomenal products, but you don’t have a way to make them and ship them, you have nothing,” said Ostuni. “If you’re just a manufacturer and have no products, then you’re a manufacturer. And there are plenty of manufacturers out there. So, we feel it’s really important to do all those three things well to make sure that the whole is greater than some of the individual parts.”
Ostuni and ARTBIO are going to have to nail those three pegs if they’re to be competitive with the likes of Novartis, which continues to wheel and deal when it comes to RLT. In November 2024, Ratio Therapeutics inked an exclusive worldwide agreement potentially worth $745M with Novartis, a collaboration that leverages Ratio’s RLT discovery and development expertise as well as its technology platforms for the development of a Somatostatin Receptor 2 (SSTR2) radiotherapeutic candidate for cancer. Novartis also acquired Mariana Oncology in May 2024, including development candidate MC-339, an actinium-based RLT being investigated in small cell lung cancer. On top of that, Novartis doubled down on RLTs by throwing $200 million to make two new facilities boost radiopharma manufacturing and market dominance.
CAR-T versus RLTs
Just because Ostuni switched from working on CAR-Ts to RLTs doesn’t mean he believes that only one will work and the other will fail. “I think the biology behind CAR-T is supremely beautiful, and it really represents the leading edge of where we’re going in terms of manipulating human cells,” said Ostuni. “CAR-T hasn’t shown a lot of ability to hit solid tumors. They’ve been great in liquid tumors. Unfortunately, the majority of tumors are solid.” Rather, Ostuni believes that there is some major potential synergy, particularly in attacking solid tumors. As Ostuni explained, “The alpha particle modality essentially creates a small explosion of antigens in the tumor, which do recruit T cells—a situation ripe with synergistic potential.”
When comparing RLTs to CAR-Ts, Ostuni finds that RLTs’ supply chains and production methods are superior. “I’ve been out of CAR-T for over three years, and back then, it was harder to move the needle sometimes on the CAR-T side,” said Ostuni. “But now that there’s a lot more automation, I expect that to also change. But in our case, the scaling can be a bit more exponential, based on how we source and batch processes, as well as how we think about the distribution of manufacturing relative to delivery, because it just becomes a game of optimizing the logistics for the volume that you have. Then at a certain quantum of volume, the expansion to additional manufacturing should pay for itself.”
Anticipation of a major new modality entering the precision medicine arsenal is fueling optimism for the next chapter of targeted oncology. The financial resources are undoubtedly available. It will be interesting to see how the safety of these radioactive drugs plays out in the long term. Perhaps the next Chernobyl is on the horizon, but this time it will happen inside people as a result of, ironically, new medications. Meanwhile, regulators, who are already tackling new modalities such as genome editing, will be tasked with overseeing what appears to be shaping up to be a huge RLT industry.
