INXN-2001

Cytokine therapies targeting IL-18 and IL-12 have long been plagued with problems. Mural Oncology thinks its protein-engineering strategy may have solved them. It’s been a busy five months since cytokine therapy startup Mural Oncology landed its first big check after spinning out of Alkermes. Besides the usual new-business housekeeping, the company is in the midst of two potentially registrational late-stage studies for its lead clinical candidate. One candidate is an engineered interleukin-2 (IL-2) cytokine called nemvaleukin alfa. One trial pairs the drug with Merck & Co.'s Keytruda to treat ovarian cancer, while the second tests it as a monotherapy for mucosal melanoma.  “We’ve been focused very diligently on making sure that we deliver on these studies,” Caroline Loew, Ph.D., told Fierce Biotech Research in an interview. “Execution is going very well on those.”  But that’s not all. Mural has some potential new additions to the pipeline as well. During the annual meeting of the American Association for Cancer Research from April 5 to April 10, the company presented preclinical data on two new programs, one for a cytokine therapy that boosts interleukin-18 (IL-18) and another targeting IL-12.  “We’re really excited because it’s the first time that we have disclosed any data on these programs,” Loew said.  Both targets have generated a lot of interest in the cytokine therapy world. Simcha Therapeutics, Gilead and others are working on anti-cancer agents that target IL-18. Gilead also recently shelled out nearly $44 million for Xilio’s IL-12 drug. But no such drugs have FDA approval yet, partly because they’re difficult to develop in the first place.  While it’s still early days, Loew believes that Mural’s candidates have a good shot at performing well in the clinic, perhaps accomplished what others have not yet achieved.  “We’re confident that [our IL-18 therapy] is engineered with a really differentiated approach that will play out significantly in the clinic,” Loew said, adding later that she believes that the IL-12 molecule has the potential to be “best in class.”  IL-18-targeting cytokine therapies are very good at stimulating the immune system. But they’re held back by their affinity for a protein called IL-18 binding protein (IL-18PB), which neutralizes IL-18 and renders it ineffective. On top of that, the cytokines don’t stick around for long—their short half-life can make it difficult to achieve a lasting therapeutic effect.  Mural has built its way around these challenges. Scientists at the company altered IL-18’s structure to remove its affinity for IL-18PB without diminishing its potency, then attached protein scaffolds to it to increase its half-life. In one of its two AACR posters, Mural showed that its “enhanced” version of IL-18 stimulated an elevated, more sustained immune response in mice than did standard IL-18, a sign that it’s working as the company hoped.  For IL-12, Mural faced a different problem entirely. The cytokine is a powerful stimulator of the immune response and is known to have significant anti-tumor activity. It’s also very toxic.  “It has a very narrow therapeutic index,” Loew explained. “There’s a very tiny, specific amount that you can deliver before you get these toxicities. So the question is, how can you actually use this?”  To answer that, Mural researchers took what Loew described as a “Lego-like” approach. They split the cytokine into two inactive monomers, which they fused to antibody fragments directed at tumor antigens. These are administered one after another so they reach the tumor site separately, then fuse back together in its microenvironment. That way, they don’t assemble anywhere they shouldn’t, thus reducing IL-12’s toxic side effects.   “You’re creating the activity in the tumor, but you’re not creating any systemic toxicity,” Loew said. “It’s like science fiction.”  The second AACR poster showed that this sci-fi mechanism does indeed play out in the real world. In the tumors of mouse models, the researchers saw that the two subunits bound together and increased the release of inflammatory molecules within them—without any systemic adverse effects.  For both candidates, the most exciting aspect of the new AACR data is that the Mural’s protein-engineering strategy is ameliorating the issues that have held these types of drugs back from reaching their full potential, Loew said.  “As with nemvaleukin alfa, we are able to mitigate the issues and unveil the efficacy potential of those targets,” she said. Mural will nominate candidates for its IL-12 and IL-18 programs sometime this year, according to the company's Q4 report.  Mural may also have cracked the code when it comes to attracting female leaders. The company’s CEO, CMO and chief legal officer are all women—an unusual C suite for the industry. Women make up only a third of C-level positions at biotech companies, a 2023 survey of life sciences professionals showed.  “There are incredibly talented women who are now ready to take leadership roles—and who have been taking leadership roles—across biotechs and pharma,” Loew said. “I think it’s incredibly important in the recruitment process that leaders take time to explore diverse slates,” not only with regards to gender and other types of diversity as well, she added.  “When you’re systematic about doing that, that’s how you always ensure that you’ve brought the best leaders to the table,” Loew said. “In our case, they happen to be women.”  Loew has noticed that companies with a female leader tend to attract more of them. She theorized that having women at the helm signifies to other would-be women leaders that the firm’s culture will embrace them. “Part of that is that women are encouraged to maybe take a step-up role, to advance their own careers. They’re feeling supported by other women,” Loew said. “I feel proud to have been able to support women in their careers over the course of mine. It’s something we’ll continue to do.” 

Gilead Sciences and Xilio Therapeutics have announced a partnership to develop IL-12 therapeutics. Credit: Tada Images via Shutterstock. Gilead Sciences and Xilio Therapeutics declared an exclusive license agreement for the development of a tumour-activated IL-12 program. Under the deal, Gilead Sciences has agreed to give Xilio $43.5m in upfront payments, including a cash payment of $30 million. Gilead will also provide a $13.5m initial equity investment in Xilio’s common stock at a premium. Later on, the clinical-stage biotech may be able to receive up to $604m in extra payments, in additional equity investments by Gilead, a transition fee and specified development, regulatory and sales-based milestones. According to the agreement, Xilio will also be eligible to accept tiered royalties varying from high single digits to mid-teens on annual global net product sales. With the new partnership, Xilio will be in charge of the clinical development of XTX301 in the ongoing Phase I clinical trial (NCT05684965) through dose expansion. Once Xilio has fulfilled its role, Gilead can choose to take over the clinical development and commercialisation of XTX301, subject to the terms of the contract and an additional $75m transition fee. Before the payment of this fee, Xilio is eligible to gain up to a total of $29m in additional equity investments and a development milestone payment. “We believe IL-12 has the potential to treat a broad range of tumour types and are excited to partner with Xilio to advance XTX301, a tumour-activated IL-12, as a monotherapy and a combination therapy across a variety of solid tumours,” said Dr Bill Grossman, Gilead Sciences’s senior vice president of oncology clinical development in the 28 March press release. See Also: Cidara Therapeutics gets grant for conjugates for treating viral infections 4D Molecular Therapeutics gets grant for recombinant aav for muscle cell infectivity with heterologous peptide XTX301 is an IL-12 activator under development for solid tumours including, head and neck squamous cell carcinoma, melanoma and non-small cell lung cancer. The therapy, which was developed using Xilio’s proprietary tumour-activation platform, acts by activating T-lymphocyte and natural killer cell proliferation, which in turn kills cancer cells. The US-based company is using the platform to develop a pipeline of tumour-activated molecules such as cytokines, bispecifics and antibodies. The latest deal with Xilio adds to a chain of deals executed by Gilead Sciences. In the last few months, Gilead has also made headlines for its deals with CymaBay Therapeutics , Merus and Arcus Biosciences.