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May 11, 2023

The Power of Immunotherapy Brings Hope to Patients

Editor in Chief Damian Doherty recently spoke with Ivana Djuretic, PhD, the

Editor in Chief Damian Doherty recently spoke with Ivana Djuretic, PhD, the chief scientific officer and co-founder of Asher Bio, about pursuing her passion for immunotherapy discoveries during an era of breakthroughs in this field

Q: When did you first become interested in immunology?

Ivana Djuretic: I always had science in my sights in my academic pursuits. I left my native Montenegro in 1998 to finish my last year of high school in the U.S. During that time, I looked for a university that would be best suited to help me further cultivate my scientific interests. I majored in biochemistry at the University of Massachusetts and took graduate level classes in immunology while I was still an undergrad. I then earned my PhD in immunology from Harvard University.

At Harvard, my studies in the field of cytokines and T cell differentiation led me to seminal discoveries. I discovered that a transcription factor called Runx3 that normally programs the CD8 T cell lineage and blocks the CD4 T cell lineage is also reinduced in CD4 T cells later in their differentiation to enable their immune functions. As part of my research, I used immune cells and cytokine genes to study how cells are programmed into different cell lineages/cell types, and showed that immune cell fate decisions are reinforced by feed-forward regulatory circuits involving transcription factors and cytokine genes. I’m proud to have had my work published in Nature Immunology, Immunity, and the Journal of Experimental Medicine.

Q: What drove your move to industry to pursue cancer drug innovation?

ID: I wanted to do something that had real impact on people, and that moved my career to be closer to developing treatments for patients. I knew from working in academia that the primary focus is often on writing papers and doing experiments to prove your hypotheses. And while important, those experiments aren't always directly related to treating patients.

So I was excited to take my first job in industry, which was at a biotech start-up focused on small molecule drug discovery. As I started to learn more about drug development, it occurred to me that maybe inhibiting one pathway with a small molecule isn't enough to cure complex diseases that might be more effectively treated with drug modalities that can impact multiple pathways.

Q: What types of drug modalities did you work on in the field of immunotherapies?

ID: I started to learn about cell therapies and their potential impact on patients, turning on and regulating multiple pathways, and this led me to Celgene. At Celgene, I led cell therapy programs with drugs created by engineered immune cells, specifically allogeneic [natural killer] cells and autologous T cells, and my work spanned from preclinical development through [investigational new drug] filing and Phase I.

Following my tenure at Celgene, I moved to the West Coast and took on the role of head of cytokine biology at Pfizer's Cancer Immunology Discovery Center in South San Francisco. At Pfizer, I advanced novel programs in cancer immunotherapy as well as being involved with leading-edge T cell redirection programs, including bispecific antibodies and allogeneic CAR-T cell therapies.

In the area of allogeneic cell therapies, I developed and tested strategies to enhance their persistence, avoid allogeneic rejection, and enhance CAR T cell activity in solid tumors. My work on bispecific antibodies included CD3 bispecifics for targeted tumor therapy, and I developed a strategy for T cell redirection with an FLT3 bispecific in acute myeloid leukemia. I also worked on immune modulating biologics, including cytokines.

Q: How did you decide to step away from roles at larger companies and become an entrepreneur?

ID: An attractive aspect of being in big pharma is there are more resources and more things to try. I was learning more about antibodies and biologics and biologic modalities, which were "in between" small molecules and cell therapies. With an immune modulator or a cytokine, you could impact multiple pathways, again, but it's more easily developable than a cell therapy.

I gravitated towards this "in between" modality where you can impact multiple pathways with an agonist. You can also rationally develop it and it's not such a manufacturing challenge as cell therapies. That's how I, and my Pfizer colleague and co-founder of Asher Bio, Andy Yeung, became interested in immune modulators and immune agonists. Pfizer closed its Discovery Center in San Francisco in 2018, and at that time, I decided to take a leap as an entrepreneur and co-founded Asher Bio with Andy.

Q: Tell me about Asher Bio and your "light bulb moment" for finding a new approach to developing immune modulating biologics.

ID: In founding Asher Bio, we thought we could address the pleiotropic limitations of first-generation interleukin-2 (IL-2) therapies using cis-targeting. Pleiotropy is a phenomenon where an immunomodulator naturally leads to activation of multiple immune cell subtypes simultaneously, without the ability to be selective. The activation of multiple immune cell subtypes can result in toxicity and, in some cases, reduced efficacy due to opposing effects of the different cell subtypes.

Our innovative approach at Asher Bio achieved cis-targeting, which is the engagement of two molecules on the same cell. Cis-targeted immunotherapy engages both an immunomodulatory receptor and a specific target that directs the therapy to the desired immune cell type. The key feature of cis-targeted immunotherapies is that they focus on a singular immunoregulatory target, which can result in an unprecedented level of selectivity for the subtype of immune effector cells that drives the desired effect—thereby overcoming pleiotropic effects.

There was one academic paper published in 2014 that described how one cytokine—interferon alpha—could be targeted to one cell type. It was just a single example. This was exciting because it seemed very achievable and the technology didn't seem too complicated, but it was early. It was only tried on one cytokine, however. We asked the big question: whether it would work on other cytokines. And if it worked on many other cytokines and it was a rule across the board, then it would be amazing to have that as a platform. Andy and I decided that this was something that just had to be worked on.

Q: How did you make progress from the initial idea to evidence that you could create meaningful drugs?

ID: As we began to do initial experiments, our approach with cis-targeting showed promise. We initially secured funding by winning a $150,000 prize from the San Francisco incubator Y Combinator, followed shortly by $1,000,000 in additional funding, which allowed us to conduct experiments to show the potential of cis-targeting. We found our results to be amazing, and we were learning how to find the right ways to utilize our cis-targeting technology in the right examples. This success allowed us to attract the interest of a blue-chip venture capital syndicate with a $55 million Series A financing, subsequently followed by a $108 million Series B financing in 2021.

Our cis-targeting approach is distinct from other targeted immunotherapies that focus their drug design on directing their therapy to the location of disease, such as the tumor microenvironment. However, in engaging receptors on immune cells, they often activate many immune cell types in and outside of the intended location, leading to a lack of selectivity to the tumor and side effects on healthy cells.

In contrast, our uniquely selective approach with cis-targeting can allow us to therapeutically target only the immune cell types that matter in treating diseases, particularly cancer.

Q: Tell me about Asher Bio's pipeline of cis-targeted immunotherapies.

ID: Our lead program, AB248, is derived from our initial work when we founded Asher Bio and explored whether reducing the pleiotropic activity of IL-2 by restricting it only to CD8 T cells—the primary effector cells of anti-tumor efficacy—would result in a therapeutic with better efficacy and lower toxicity. Based on this promising work, we engineered AB248 as a novel CD8+ T cell selective IL-2 that activates and expands CD8+ tumor killing T cells, while avoiding natural killer cells and regulatory T (Treg) cells. It is currently being studied alone and in combination with a PD-1 inhibitor therapy in patients with advanced solid tumors who failed prior standard of care treatments.

AB248 demonstrated highly compelling anti-tumor activity in multiple preclinical tumor models, showing superior efficacy to other IL-2 therapies currently available and in clinical development for the treatment of cancer. In contrast to native IL-2, AB248 drives selective, unparalleled expansion of CD8+ T cells. AB248 elicits minimal activation of Tregs, which counteract productive immunity, and minimal activation of other IL-2 responsive cell types that may contribute to dose-limiting toxicity.

We are also advancing AB821, a CD8-targeted interleukin 21 (IL-21), designed to selectively activate CD8+ T cells via a pathway distinct from and complementary to IL-2. IL-21 enables T cells to kill tumor cells more effectively by enhancing their cytotoxic function.

Beyond AB248 and AB821, we have rapidly developed and are advancing a pipeline of immunotherapies to address patient populations with unmet medical needs. While our primary focus is on oncology, the modular nature of our cis-targeting platform allows us to leverage other immunomodulators and immune cell types to expand into additional therapeutic areas, including infectious and autoimmune diseases.

Q: What have been the most rewarding and challenging aspects of being an entrepreneur?

ID: I would say there's nothing like this. When you’re fully responsible for all aspects, it's both challenging and rewarding to start with an idea and make progress to create a product. I would say there's nothing that gives you such joy [as] to be there from the idea to how it evolves to the product, working closely with a small team and being fully responsible for the results.

One thing that helped along the way is the great advice from colleagues and friends. I’m now happy to share my insights and my experience with others as they begin their journeys. We all encounter the same problems, and having a network to learn from and share advice is invaluable for everyone.

Q: What is the origin of the name Asher?

ID: "Asher" means hope, health, and happiness—which is exactly what we hope to restore in the lives of patients with our novel approach to immunotherapies. At Asher, we’re doing something that aims to have important impact, and has allowed me to be as close as you can get to developing treatments for patients.

Damian Doherty has been in media and publishing for nearly 30 years, beginning in the early nineties at News Corporation. Damian has managed, edited, and launched life science titles in drug discovery and precision medicine. He was features editor of Drug Discovery World for fourteen years and founded, established, and edited the Journal of Precision Medicine in 2014. In parallel, Damian founded and organized the Precision Medicine Leaders’ Summit, a global, immersive 3-day senior leadership conference that still runs today. He edited AIMed magazine in 2019 before launching Photo51Media, a platform for illuminating untold, compelling stories in precision healthcare. Damian joined Mary Ann Liebert in 2021 to help steer the new rebrand and relaunch of Clinical OMICS to Inside Precision Medicine

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