EpiBiologics: Rami Hannoush
"We came together with a unified vision to build EpiBiologics as a pioneering company in the extracellular degradation space."
I do not spend too much time thinking about garbage.
My apartment building has a chute for trash, and bins for recycling—plastic, paper…pretty simple. Once that chute snaps shut, my deposited bag of detritus is on its own—out of sight and out of mind.
The average cell is considerably less fortunate. Taking out the garbage is a complex affair—quite literally a matter of life and death. If our intracellular garbagemen or processing plants falter, biomolecular waste can spew into the cytosol and cause cell death.
Nature takes two major routes on protein “garbage day”—the ubiquitin proteasome pathway, and lysosomal proteolysis. The first route is more familiar to drug developers: a ubiquitin ligase attaches a small tag to a protein that marks it for destruction in a macromolecular meat grinder called the proteasome (“processing plant”). The proteasome chops the protein into very small peptide fragments, which can be re-used by the cell. Therapeutics called proteolysis targeting chimeras (PROTACs), bring a “target” into close proximity with a ubiquitin ligase “garbageman”—increasing the chance that the protein is tagged and sent to the proteasome. Though there are no FDA approved PROTACs, there are dozens in clinical development, primarily in oncology.
Lysosomal degradation works differently—these are sacs containing digestive enzymes (proteases) that destroy proteins unlucky enough to be trapped inside. Extracellular proteins (and some cytosolic ones) that bind a “recycling receptor” on cell membranes, can be internalized and shuttled to the lysosome: “Nature has used these recycling receptors for billions of years to regulate the levels of secreted proteins and those on the cell surface. This is a mechanism that's been conserved throughout the animal kingdom,” explains Rami Hannoush, interim CEO and co-founder of EpiBiologics.
Exploiting these “natural” garbage routes to destroy pathogenic proteins is a well-accepted therapeutic strategy—especially for disordered targets, or those hidden within lipid membranes: “Many of these [cell surface or extracellular] proteins are known to have scaffolding roles and are not amenable to functional blockade by just standard antibody or small-molecule approaches,” explains Hannoush. Yet coaxing the cell to “toss” these high value targets into the garbage, is easier said than done. Recent research from James Wells’ lab offered two potential ways forward: one technique (AbTAC) uses a bispecific antibody to bring a membrane bound E3 ligase into proximity with a cell surface protein, and target it for proteasomal degradation (garbage route 1). A second bispecific antibody approach (kineTAC) brings a target of interest into proximity with a recycling receptor, ultimately condemning this protein to the lysosome (garbage route 2).
Based on this work, EpiBiologics was founded in 2021. The company seeks to therapeutically traverse these two garbage routes, to degrade proteins that have historically evaded drug developers: “We are really excited about advancing this work forward to establish clinical proof of concept in humans,” says Hannoush.
Their work is cut out for them: there are hundreds of potential garbage “chutes” (recycling receptors or membrane bound E3 ligases). Nature has engineered specificity into the system—not every chute will accommodate a particular piece of protein trash. An empiric approach is needed to find optimal target and degrader pairings: “We have built an atlas of degrader receptors that span multiple tissues and cell types. In parallel, we have industrialized a combinatorial approach that enables us to screen the entire atlas of degraders to identify the optimal molecules against particular cell-surface or extracellular targets of interest.” Past approaches (e.g. PROTACs) that rely too heavily on a single chute (e.g. an E3 ligase) have met with difficulty: old-age, disease or genetics often can disrupt individual garbagemen. With its atlas and screening platform, EpiBiologics seek to find the best degrader for the job: “we have an opportunity to go into unexplored biology and uncover mechanistic differences between degradation pathways and how those might translate into therapies.” To support their work, EpiBiologics recently announced a $50 million series A financing, which was co-led by Mubadala Capital and Polaris Partners, with participation from Vivo Capital and GV.
Dr. Rami Hannoush is a co-founder, President and interim CEO of EpiBiologics. He also recently joined Versant Ventures (as a venture partner) where he works on biotech company creation and life science investments. Born in war-torn Lebanon and trained as a chemical biologist at McGill and Harvard, Hannoush is a 15-year Genentech veteran: “Multiple aspects of the culture we built at EpiBiologics are reflective of my experience at Genentech.” He shares stories from his upbringing, advice to science trainees, and broad thoughts on science and biotech in a previous Biomarker interview [Nov ‘22].
The next time you take out your trash, consider: how long will it take to get picked up? Which garbagemen will collect it? How fast will they drive to the dump, and will they take the most time-effective route? Are there differences in rate of decomposition between different landfills? And of course, the perennial—did you sort your recycling properly?
Perhaps an out of sight out of mind approach is best. Yet rest assured that Hannoush and his team at EpiBiologics are trying to answer these questions in minute detail, albeit on a cellular level. In the process, they seek to uncover new truths about biology, identify novel drug candidates and, above all else, help patients suffering from oncologic and inflammatory disease.
Below is an interview with Rami Hannoush, interim CEO and co-founder of EpiBiologics and venture partner at Versant, from April 2023:
1.) Since our interview last November (2022), what are the major updates on your role as an investor?
I’m happy to announce that I joined the investment team at Versant Ventures. As a venture partner, I am focused on early-stage healthcare investments and company creation. I'm most excited about continuing to work with academic founders and exceptional entrepreneurs to build the next generation of biotechnology and life science companies.
Over the past couple of years, I've been involved in building a number of these companies, including EpiBiologics, which we will discuss today. At Versant I will continue to be involved in building companies that are using cutting-edge approaches to discover novel therapeutics. I came to Versant because of the scientific and investment acumen, the business rigor of the team, and the firm’s collaborative spirit.
Versant has discovery engines, which is unique among the biotech VCs. These engines comprise in house teams of multidisciplinary scientists that work in state-of-the-art laboratory facilities to enable the launch of new companies. As part of my new role, I'm also excited to be working closely with these teams. [This approach] really gives us an edge in terms of testing and validating ideas early on before launching companies.
My day to day involves a number of activities with a broad scope: I work closely with the founders and the management teams of portfolio companies, providing strategic, business and scientific support for these companies. In parallel, a substantial portion of my time is also spent on ideation and new company formation in close collaboration with other partners and the discovery engine at the firm. I also spend time cultivating and evaluating new opportunities for potential venture investments in the biotech and healthcare sectors. [My role at Versant] encompasses a mix of responsibilities which include company creation, life science investments and managing portfolio companies and it is highly collaborative in nature, working with other partners, investors, founders and pharma.
2.) You are co-founder and interim CEO of EpiBiologics—what was the founding story and vision? What were your initial conversations like with Jim Wells, and when did it get serious traction?
Our conversations started back in the summer of 2021, when I was getting ready to leave Genentech after a 15-year career in drug discovery and development. I met with Jim Wells over coffee—Jim and I have known each other for a long time through collaborations between Genentech and UCSF. We have both worked in the field of protein engineering and drug discovery and share a lot of common interests and scientific views. At the time, Jim mentioned the idea of degrading proteins on the cell surface by leveraging cytokine receptors—hijacking normal internalization and recycling mechanisms. I was intrigued. Nature has used these receptors for millions of years to regulate the levels of receptors on the surface and secreted proteins. This is a mechanism that's been conserved throughout the animal kingdom. The idea of recapitulating what nature has done for millions of years using synthetic antibodies seemed compelling. We started to get serious about building the company in early Fall of 2021. With Polaris Partners, we started to map the business and scientific strategy for what a company build might look like. But we recognized that we needed to bring in other investors at this early stage of ideation of the company. We built a strong syndicate of investors, partnering with GV [David Schenkein] and Vivo Capital [Mitchell Mutz]. Mitchell used to be at Roche Ventures and David was at Genentech; so there were a lot of old Genentech connections coming together.
All the investors at the table were formally trained as scientists. We came together with a unified vision to build EpiBiologics as a pioneering company in the extracellular degradation space. There were a number of pieces that needed to come together before this could happen: the licensing of IP from UCSF, finding the lab space to conduct research, setting up the lab, ordering the first instruments to enable protein production and purification, setting up the IT infrastructure, and most importantly hiring the team. This process took around four to five months before we officially launched in an incubator space in San Carlos. I stepped in to take an operational role as the interim CEO and CSO to build the company and start recruiting a team of talented scientists.
At the time [2021-2022], I was working full time as a general partner at Mubadala capital. This was the first company incubation that was done at the firm. I leveraged my prior experience in building and running effective R&D teams at Genentech to build the company and get it off the ground.
[On interim CEO position]
The role entails building the company from the ground up, establishing the culture of the company, the corporate and business strategy, and the hiring plan for both the scientific and operations teams — bringing all the pieces together to enable execution on the platform technology and building the drug development pipeline. Developing the strategic and financial trajectory for the company over the next two to three years is an equally important aspect of my role. Additionally, the hiring process itself takes time—to attract a permanent CSO or CEO for the company. [As interim CEO] you need to build a hiring plan that forecasts where the critical skill sets and needs are going to be for the company at different points in time.
3.) Historically what has been difficult about targeting extracellular proteins? Which approaches have been tried in the past, if any, to degrade these difficult to reach targets?
I'll start with explaining the name of the company. “Epi” means above or over, referring to proteins that are on or above [outside] the cell surface. This is really the class of proteins that we are interested in targeting. The idea of targeted protein degradation has existed over the past two decades, as a promising therapeutic strategy. There are advantages over conventional inhibition, which relies on occupancy driven pharmacology. In other words, a ligand or a molecule needs to occupy a certain pocket that mediates activity of a protein or its interactions.
Degraders could be catalytic, in certain cases, and also can provide durable knockdown of protein levels. We focused on the cell surface proteins that don't have defined regions or ligands to go after [via conventional approaches]. Many of these are proteins that are known to have scaffolding roles and are not amenable to functional blockade by just standard or classical antibody approaches. In oncology, many receptors on the surface have high rates of resistance mutations to standard therapies. Many of these are also difficult to drug because they are multidomain transmembrane proteins that have large regions inaccessible to antibody therapeutics. So, when you think about the universe of targets on the cell surface and also secreted proteins—it constitutes about 40% of the proteome. We thought a degradation approach might be beneficial in going after these classes of proteins that have been intractable by using standard antibody binders. There have been a number of early efforts in the field demonstrating that one could degrade extracellular targets in vitro and to a more limited extent in animal models. We are really excited about moving this work forwards to establish a proof of concept in humans, which is what EpiBiologics strives for.
The scientific rationale of EpiBiologics is based on leveraging bispecific antibodies: one arm of the antibody would bind to a degrading or recycling receptor of interest. The other arm would bind to a disease-causing protein of interest. Through receptor-mediated internalization or ubiquitination on the cell surface, the target protein of interest would be marked for intracellular degradation. Just to reiterate--we are using an established modality [a bispecific antibody] to remove a target protein from the surface rather than a more untested approach.
What is unique about EpiBiologics, is that we have built an atlas of these degrader receptors that span multiple tissues and cell types. In parallel, we have industrialized a combinatorial approach that enables us to 1) produce bispecific antibodies in a high throughput manner and 2) screen the entire atlas of degraders to identify the optimal molecules against particular cell-surface or extracellular targets of interest. This integrated approach enables us to rapidly zoom in on the optimal degraders, discover initial hits and then move rapidly to lead optimization stage of a bispecific antibody therapy.
One of the compelling features of this approach is taking an established antibody modality [antibodies] –for which there has been a number of approved molecules on the market. This modality is relatively low risk in terms of developability of lead assets down the road. This is a significant consideration when building a company: one needs to manage the risks of the biology, the risks of the platform, and also the risk of manufacturing and development for the molecule itself.
4.) What are the key scientific advances behind EpiBiologics? What is the “secret sauce” that will enable you to go after difficult to reach targets?
What’s unique about EpiBiologics is the atlas of receptors, combinatorial approach, and optimal molecule formats against particular proteins of interest. We are using an established antibody modality for which there has been a number of approved molecules of similar formats on the market. So that format itself provides for low risk in terms of developability down the road. And, and that [established modality] is a significant consideration, as we manage the risks. So it [secret sauce] is really several factors: the Atlas itself, screening in high-throughput combinatorial fashion and using an established modality to develop lead assets.
5.) For a given membrane-bound target, will you be pursuing both antibody-based PROTACs (AbTACs) using membrane-bound E3 ligases AND KineTAC bispecifics that can deliver to the lysosome in an E3 ligase independent fashion?
We are agnostic to which approach [AbTAC vs KineTAC] to pursue against a particular target of interest. The platform itself encompasses the KineTAC and the AbTAC approaches, and an additional [unpublished] component that has been built internally at the company over the past year. Given the disease context and target product profile that we are aiming for, we will screen the entire atlas of degrader receptors, which enables us to empirically select the ones that are most suitable for a specific target. You could think of specific tumor types or immunological disease where some degraders from one platform might perform better than degraders from another platform, and vice versa. We will discover this through our development process.
6.) In the Pance et al., 2023 article from the Wells lab: the CXCR7 decoy recycling receptor was used to target a range of proteins to the lysosome. What is the universe of decoy recycling receptors like?
We are looking at many of these receptors, like CXCR7. In the case of the KineTAC platform there are a number of cytokine receptors that could be leveraged in a manner that is similar to CXCR7. But as you mentioned, adjusting the different epitopes, affinities and valencies for binding quickly expands the combinatorial world of possibilities. This is why we have invested a lot of effort initially in building and enabling the infrastructure to carry out high throughput screening. We will continue to explore that universe of degrading receptors. Mapping this universe and the best combinations is an area that is actively being pursued at EpiBio, so that we can best understand the internalization and recycling capacities of the different receptors.
[Are there endo-lysosomal escape pathways present for some recycling receptors, and might this lead to inefficient degradation?]
It's a great point. We have found that there is a balance between recycling and targeting to the lysosome. It is one of the important aspects that we pay special attention to in our screening strategy to enable us to discover molecules that meet the required target degradation levels. There are different capacities [balances between degradation and escape] amongst recycling receptors and protein target pairs.
We analyze the endosomal escape pathways in depth to understand how it impacts the efficiency of degradation towards a particular target protein of interest. One also needs to consider the dynamics of the target protein of interest, because that could also alter the native initialization and recycling mechanisms for the degrading receptor itself. We look at partners [target and degrader receptor], and this is factored into our secondary assays as we screen.
[I'm predicting, there are going to be some amazing papers that additionally come out of this company and platform as well.]
This is one of the things that got me most excited about this company, because there's so much undiscovered biology regarding cytokine receptors and ubiquitin cell surface ligases. So [EpiBiologics] really provides an opportunity to go into unexplored biology and uncover mechanistic differences between traditional inhibition approaches and degradation pathways and how those might translate to therapies for human patients.
7.) For extracellular targets (non-membrane bound), does it matter what cell-type performs the lysosomal degradation? Does it matter in which specific cell type the “garbage truck” is located?
Absolutely the location matters. In society we would want to route the garbage truck to an area where we want to get rid of the trash, right? For EpiBiologics, this “ideal location” is going to be target dependent. The mechanism and efficiency of degradation should meet the desired target product profile for a particular disease indication. In some cases, degrading the pathogenic proteins in the liver might be appropriate. And in other cases, degrading the target in specific tissues—whether it is the lung or colon—might be more desirable to achieve an appropriate therapeutic index. This goes back to the platform’s atlas, which gives us a lot of optionality. We can select the degraders that are either tissue specific or have broad distributions, to achieve the desired potency, efficacy and safety.
I'm excited to the potential applications and the translatability of the platform to advance drug candidates to the clinic. The screening capabilities combined with the atlas, give us a unique opportunity to quickly identify functional antibodies that could degrade proteins that are intractable by classic approaches.
8.) In our last interview you spoke about a company build that was underway: “One of the most important aspects in company creation is to build an inclusive culture with a strong vision…people are the greatest assets in a company.” Can you speak to some of the people involved in EpiBiologics? How are their unique expertise positioning the company for success?
From day one, we focused on building a culture that emphasizes inclusiveness, transparency, scientific rigor, and data driven decisions. Multiple aspects in this culture are actually reflective of my experience at Genentech. Setting the right tone for the culture from the beginning goes a long way in building a sense of belonging, connection and common purpose. Everyone at EpiBiologics, regardless of their position and title, is expected to contribute their ideas and share their opinions in a constructive manner. We've done this from day one. We have just gone from 0 to over 20 employees, and have built a talented team with core expertise in protein engineering and biology. Kudos to the first employees who joined the company. Together, we worked hand in hand to lay out the foundation for the company. More recently, we're fortunate to hire Shyra Gardai, as the new CSO for EpiBiologics. Shyra was the former head of Discovery Research and Therapeutics at Seagen. We're excited to have her on board, because she brings a wealth of experience in drug discovery and development, in addition to being a terrific leader who is aligned with the culture we have built at the company.
9.) Where do you envision the company in 5-10 years? What currently has you most excited as interim CEO, about this venture?
We envision EpiBiologics to be a clinical stage company with a number of assets, both in human trials and late-stage non-clinical development. Our vision is for the company to be a leader in extracellular protein degradation. To get there, it's going to be important to continue to strategically balance and manage the risks on both the platform and target selection side. Equally important, thinking about commercial risks early on could have a big impact on the types of differentiated products we want to create in specific indications with high unmet need. I'm personally excited about the progress that's been made so far: we have gone from an idea to an industrialized platform and built an integrated atlas of degraders with ongoing proof of concept studies and pipeline programs. All of this can’t be achieved without a truly special and talented team at the company and the support of the investor syndicate and the academic co-founders. I'm proud of how far we have come along, working together through different aspects of building and enabling the company, de-risking the science and getting to a point where we have enabled antibody degrader drug discovery.
