AstraZeneca has been busy in recent years pumping up its oncology pipeline via a shopping list of assets and companies. Now, the U.K.-based pharma is overseeing a range of clinical trials to determine whether these cancer bets will pay off.
“We have deliberately made investment in the next-generation technologies which we believe will redefine oncology care, like ADCs [and] radioconjugates,” Puja Sapra, Ph.D., AstraZeneca’s senior vice president for biologics engineering and oncology target discovery, told Fierce Biotech in an interview.
AstraZeneca already has a reputation when it comes to antibody-drug conjugates, having turned Enhertu into a blockbuster and then following it up with the FDA approval of another ADC, Datroway, in January.
While both Enhertu and Datroway emerged from a collaboration with Daiichi Sankyo, Sapra said the next chapter of AstraZeneca’s ADC story involves “a conscious effort to invest significantly” in its internal pipeline.
This has resulted in a clinical-stage line-up of six in-house ADCs aimed across solid tumors and hematological malignancies. AstraZeneca arrived at the European Society for Medical Oncology conference in September 2024 armed with data from two of these: a folate receptor α (FRα) -targeted ADC called AZD5335 and a B7-H4–directed topoisomerase I inhibitor ADC called AZD8205.
“This was the first time we had put our proprietary linker-payload technology in the clinic and presented it,” Sapra said.
AZD5335 is currently in a phase 2 trial for ovarian cancer and lung adenocarcinoma, while AZD8205 is in its own mid-stage study for solid tumors.
Sapra singled out the data for AZD5335 that was shared at ESMO as “very encouraging.” AbbVie already has a FRα-directed ADC on the market in the form of Elahere, which is approved for high FRα-expressing platinum-sensitive ovarian cancer.
“We believe with our molecule … we have an opportunity to go into the entire setting of high folate receptor, as well as low folate receptor in ovarian cancer and other indications,” Sapra explained.
AstraZeneca plunged into the radiopharmaceuticals space via the acquisition of its partner Fusion Pharmaceuticals one year ago. Since that buyout, AstraZeneca has ushered a PSMA-directed radioconjugate, dubbed FPI-2265, into a phase 2 trial in prostate cancer. An EGFR-cMET targeted radioconjugate that resulted from the previous partnership with Fusion has also entered dosing in a phase 1 trial.
“It's very, very early days, but we are keeping our fingers crossed to see the first imaging data and responses,” Sapra said of the phase 1 study.
Along with a radiopharma pipeline, the buyout included Fusion's radiochemistry expertise and a manufacturing plant in Ontario, Canada. Sapra said integrating these aspects into the AstraZeneca family is going “very nicely," noting that there are also several preclinical programs tied to the acquisition that are currently in development.
Another red-hot R&D area is bispecific antibodies, a therapeutic class that has become an integral part of AstraZeneca’s cancer strategy in recent years. But with BeiGene the latest in a long line of biopharmas abandoning anti-TIGIT antibodies, does Sapra still have confidence in its PD-1/TIGIT bispecific rilvegostomig?
“I can wear my biologics engineering hat now and tell you how we designed the molecule, because it’s all in the design,” she said.
“TIGIT accesses the same immunosuppressive pathway as PD-1,” she continued. “Now you're blocking both the targets at the same time, and it should hopefully help us increase the response rate and durability.”
Rilvegostomig is designed to reduce Fc effector functionality. The Fc domain's functions are key in helping antibodies drive an effective immune response against a pathogen, Sapra pointed out, “so this should help with unwanted side effects.”
“[With the] combination of these two properties, we believe we have a very differentiated molecule," the AstraZeneca leader said.
In addition to rilvegostomig, the pharma is also developing a CTLA-4 and PD-L1 bispecific called volrustomig. The two candidates are being evaluated in a total of nine phase 3 trials between them.
“They are very different designs,” Sapra said. “They go after different population settings and that's why we are trying to maximize and put [them] in different settings.”
One of the latest trends in Big Pharma dealmaking is T-cell engagers, and here AstraZeneca has had something of a head start, thanks to the acquisition of TeneoTwo in 2022. The main asset from that deal, a CD19xCD3 T-cell engaging bispecific antibody, remains in clinical development, but alongside that AstraZeneca is now working on a CD20 T-cell engager that has recently entered human trials.
“We are also thinking about using conditional activation and masking technologies to go after targets which you may think may not be accessible with T cell engagers,” Sapra said.
When it comes to cell therapies, the Big Pharma turned heads last month by acquiring EsoBiotec and its “in vivo” capabilities.
AstraZeneca currently has seven cell therapy programs in the clinic, led by a BCMA and CD19 dual-targeting CAR-T for multiple myeloma acquired as part of 2023’s Gracell acquisition. However, executives at the Big Pharma told Fierce as far back as 2022 that they were interested in exploring the off-the-shelf—also known as allogeneic—cell therapy space.
The dedication to the space comes amid an industry reckoning, with several other pharmas—such as Takeda, Pfizer and Roche—backing away from cell and gene therapies in recent days.
“We have made broad commitments to cell therapy, and that's clear from EsoBiotec, but other things also,” Sapra said. “We have gone from autologous to building the allogeneic [and] now thinking about in vivo. So this is a long-term vision to be in this space.”
From ADCs to T-cell engagers and beyond, a flurry of dealmaking in recent years has left AstraZeneca with a wide-ranging oncology portfolio with plenty of potential. This diversity is deliberate, according to Sapra.
“That's by design, which we are very proud of,” she said. “It has been built on solid, binary scientific foundations.”