Dr. Michael Torres, CEO and founder of CrossBridge Bio, dives into the latest advancements in the ADC space, highlighting exciting innovations and his company's mission to address current gaps in cancer treatment by deploying multi-payload ADCs. Beyond groundbreaking science, Dr. Torres sheds light on the dynamic growth of Texas' life sciences ecosystem, underscoring statewide efforts and philanthropy initiatives driving unprecedented support for innovative enterprises.

Thank you for taking the time to talk with us, Michael. Can you please start off by providing us with a brief description about yourself and your path, as well as how and why you founded CrossBridge Bio?

My career in science and entrepreneurship began at the NIH, where I received an undergraduate scholarship that funded my education. As part of this program, I spent a summer conducting paid research in a renowned lab focused on DNA damage, repair, and replication stress. This experience ignited my passion for scientific research. Subsequently, I pursued a PhD at UT Southwestern, where my interest expanded into biotech trading and investing. Utilizing platforms like Twitter, I engaged in discussions about biotech's business aspects, gaining valuable insights.

Upon completing my PhD, I was keen to start a company, particularly in cystic fibrosis, an area of personal interest. At UT Southwestern, I collaborated with Professor Phil Thomas, a co-founder of Reata Pharmaceuticals, to establish ReCode Therapeutics alongside Dr. Daniel Siegwart and Dr. Arthur Johnson . Securing substantial funding, notably an $80M series A round in 2020, I assumed the role of VP of R&D, overseeing our cystic fibrosis program in Dallas. Over time, ReCode expanded significantly, progressing into clinical trials and marking a significant milestone in my career. Eager to advance in biotech leadership, I transitioned to an Entrepreneur in Residence role in Houston within the Texas Medical Center, renowned for its prestigious institutions like MD Anderson and Baylor College of Medicine. In this capacity, I managed an accelerator facilitating the commercialization of technologies from across Texas. During this tenure, I encountered the linker technology which would later form the foundation of CrossBridge Bio. I was impressed by its potential, and I evaluated the technology and collaborated closely with its academic founders.

This experience culminated in my decision to join CrossBridge Bio as CEO, embarking on the journey to build the company from inception to its current stage of development.

‍

Impressive. Were you specifically aiming to enter the ADC space? How do you view the broader ADC landscape?

I wasn’t particularly focused on entering the ADC space. My interest was in returning to oncology. During that time, I saw impressive assets through the accelerator, such as a protein-based approach for cell therapies with compelling in vivo data and exciting RNA editing technology. As part of my process, I evaluated several technologies and engaged my network in discussions about my interests to stay current in the field. This was about a year and a half ago, so the ADC field wasn't as prominent as it is now. I began speaking with ADC experts around the time Daiichi and AstraZeneca’s Enhertu data were emerging. It became evident that ADCs were becoming an important new area of focus due to the exciting clinical data emerging. As I delved deeper into novel linker and dual payload approaches and the technological innovations behind them and considered the scientific founders involved, it became increasingly clear that there was significant potential. Conversations with RA Cap, Vida Ventures, MPM, and pharmaceutical companies like Pfizer and Amgen further illuminated the landscape. Early on, I heard that while numerous ADC assets were available, there was also a lot of noise. Identifying potential winners was challenging. An investor passed on us about a year ago, asserting, “We believe the ADC boom is over. We don’t see where the next breakthrough will emerge.” However, innovation continues, and I believe the key challenge and opportunity lie in deeply understanding the current limitations of ADCs. What technologies exist to overcome these limitations? From there, can we craft a compelling narrative around a program that appeals to clinicians and investors?

‍

The ADC has definitely not been experiencing any slowdown; if anything, innovation continues to explode.

What do you see as the main unmet needs in the ADC space? Also, what do you think will be the next frontier of ADC advancement?

Taking a step back to consider where we stand today, drugs like Padcev have significantly altered practices in our field. Over several decades, the antibody, linker, and payload components have continuously refined. However, this journey has been fraught with challenges—payloads often proved too potent, linkers unstable or targets insufficiently specific, contributing to numerous setbacks that persist today. While advancements have improved progression-free and overall survival over traditional systemic chemotherapy, concerns remain regarding safety issues such as payload de-conjugation and off-target toxicity. Consequently, the field continues to address these issues collectively.

Moreover, introducing drugs with diverse mechanisms of action offers a potential strategy against resistance. By employing multiple payloads, each targeting different vulnerabilities, we may mitigate the development of resistance observed with single-agent therapies. The ability to adjust potency and induce a bystander effect further enhances the potential of these drugs against cancer, provided they can be safely delivered and activated at optimal times. Such innovations could pave the way for markedly improved ADCs compared to current offerings.

The payload itself remains a critical area of concern. While MMAE remains prevalent, recent successes with topoisomerase payloads, exemplified by Daiichi, are prompting a shift in focus. Many companies now advocate for more stable linkers, arguing that they offer superior performance. Conversely, others propose refined versions of MMAE, claiming reduced toxicity. Yet, the clinical significance of these incremental changes remains uncertain.

‍

It's clear that while significant advancements have already occurred, more are forthcoming and necessary to address outstanding unmet needs. Could you provide an example of how this might manifest in practice, including use cases and advantages of your multi-payload approach over conventional single-payload ADCs?

What's intriguing about a multi-payload approach are the concepts one could employ to drive better outcomes. The field is considering antibody concepts to enhance selectivity, but I’ll return to that shortly. For instance, combination therapies have proven effective. There's a lengthy history of synthetically lethal chemo drugs; PARP inhibitors and BRCA mutations serve as prime examples. With dual payloads, assuming appropriate safety — which is crucial — you can consider drugs that can cause DNA damage, such as topoisomerase inhibitors. Additionally, secondary payloads could further boost the efficacy of these drugs or drive cells further toward DNA damage and genomic instability. This concept already exists, and we believe there's an opportunity to integrate it with the selectivity of an antibody to create drugs that can better target tumor cells and their inherent vulnerabilities.

Another compelling concept involves using payloads to upregulate antigens. Research has shown that certain antigens can be downregulated; for example, there is data on TROP2. Drugs like epigenetic modulators can enhance or upregulate an antigen, potentially increasing the effectiveness of your ADC if paired with a cytotoxic payload. These are just two examples; we're exploring others in the lab and believe that having two payloads could unlock intriguing concepts. Logic gates represent another idea: if a specific genomic mutation makes the cancer sensitive to drug one, and that drug enhances sensitivity to payload two, you might achieve better selectivity for tumor cells over normal cells. Your choice of payloads can drive this process as well.

‍

Those concepts are really interesting. It’s fascinating to contemplate all the potential applications. Clearly, it's at the cutting edge, so challenges are inevitable. On that note, what do you see as the greatest hurdles that companies working on multi-payload approaches face?

I can be pretty candid. We've spoken to many, and the biggest question today revolves around safety. Broadly speaking, the concern is that using two drugs could double the potential for toxicity. Therefore, generating non-human primate data is a crucial milestone for our company and our linker platform. Our initial data indicates that we may achieve a better safety profile and improved therapeutic index through enhancements to the linker and its stability. Additionally, our ADCs are conjugated site-specific, and our antibodies are Fc silent, another critical aspect. The safety outcomes will likely depend on the specific combination of payloads. A combination that works well for certain cancers and genetic backgrounds might prove toxic in others. We are dedicating considerable effort to exploring multiple payload combinations to provide greater flexibility and to target better the cancers we aim to treat.

Moreover, if a payload combination demonstrates efficacy across multiple diseases — following a strategy similar to Daiichi with deruxtecan, which targets various tumor types — we would also seek to validate this in preclinical studies. Ultimately, as we make these decisions, our linkers' safety is paramount, ensuring that our platform can progress to human trials.

‍

We've discussed extensively the advantages of the multi-payload modality compared to the conventional single-payload approach. Where do you see multi-payload ADCs having the greatest opportunity and being best suited? Conversely, are there any applications where you believe single-payload ADCs might still be preferable?

As datasets mature, we will better understand the clinical improvements achievable with a homogeneous ADC with site-specific conjugation compared to cysteine conjugation, such as seen with Seagen or Daiichi’s Enhertu. If MMAE or MMAF proves too toxic, targeting the same site with a superior linker and a topoisomerase inhibitor might yield a more effective drug, potentially meeting clinical standards. Thus, the extent to which a single payload concept can succeed remains uncertain. I believe there may be limits to its effectiveness. Clinicians are now considering sequencing ADCs, administering one after another. This approach varies payloads and targets. Emerging data suggests that subsequent ADCs generally yield shorter responsiveness, progression-free survival (PFS), and overall survival compared to the initial ADC. Clinically, these are challenging questions to address. Regarding multi-payload ADCs, we believe having payloads with different MOAs or that target different pathways could be an effective one-two punch that could also address tumor heterogeneity and resistance.

Another consideration is non-oncology applications and non-cytotoxic payloads. Depending on the intended outcome and the indication being pursued, a single payload might suffice.

For us specifically, the effectiveness of delivering a well-designed combination of drugs to the tumor, with a good linker, remains to be seen. Our hope and hypothesis are optimistic: in some of our preclinical models targeting TROP2 or HER2, for instance, we observe complete response rates. We have data extending up to 150 days after a single low dose, showing no tumor recurrence with our dual-payload technology.

‍

We are also interested in getting your perspectives on the Texas life sciences landscape, which has experienced significant growth. As an enthusiast and advocate within this space, how do you perceive the current landscape, what factors have contributed to its growth, and what developments do you foresee in the future?

The great thing about Texas is that there have been world-class institutions here for a long time. Whether it's UT Southwestern in Dallas, MD Anderson, UT Health Houston, or others, Texas has always been a great scientific hotbed of technologies.

The two pieces missing are investor interest in building locally and talent that wants to be in this ecosystem. From the talent point of view, COVID and other factors have made it easier to be located elsewhere. Also, there are now more companies, and CPRIT has been a big driver of this, drawing people. Now they're willing to come, they can have a good quality of life here. And then there are more and more investors who are interested in building. We’ve got Portal Innovations and other funds that are spending time in Texas and finding that the team is here, they've got cool technology, and the tech transfer offices are facilitating the licensing of these technologies. That has really started to pick up, and I expect it to only get better because we're sitting on great research institutions and clinical care. Houston’s Helix Park infrastructure to support the companies is also here. As a side note, this is a hotbed already if you're in the cell and gene therapy space. We’ve got Lonza, CTMC, Fujifilm, and more. If you want to develop cell therapies, viral vectors, viral therapies, or biologics, the manufacturing is coming on strong.

There are very few places that have all of the parts and pieces, and that’s why I chose to move here, specifically to Houston. Another highlight of Houston is the ability to network with outstanding clinicians from MD Anderson. Since moving here, I’ve gotten to personally know oncology leaders like David Hong, Cathy Dumbrava, Chris Flowers, and John Heymach, to name a few. Leveraging their clinical insights and, in the case of company builders like me, giving them insights on how to move their ideas toward the commercial setting sets up a fantastic situation. I’m extremely bullish on what’s being built here in Texas.

‍

Fascinating. How has philanthropic and governmental support contributed to the growth of the life sciences industry in Texas?

There are a lot of initiatives in place. The efforts by Lyda Hill and Dallas philanthropies had done amazing groundwork to help the Texas Legislature adopt tax incentives that are in line with states like North Carolina with its Research Triangle Park, enabling manufacturing and biotech to grow there. Texas is catching up slowly but surely on the legislative, company-friendly side for biotech. And for oncology, CPRIT is this massive machine. I think it's the second largest funder of cancer initiatives, whether it's academics, core facilities, the accelerator that I was a part of, or the $70 million per year they give to companies. It took some time, these things don't happen overnight. But now the green shoots are emerging strongly. A lot of that is driven by state-funded initiatives.

‍

We're really interested in hearing what the future holds for CrossBridge Bio. Can you give us an overview of your pipeline, your candidates, and the approach that you're taking in your pipeline strategy?

We strongly believe that the choice of targets is crucial. In the ADC space, many of us feel that HER2 is well-covered. Padcev appears promising for Nectin-4, and there's notable activity around other targets. For CD79b, Polivy is available, and Elahere targets folate receptor-alpha. We aim to balance risk and innovation. Our strategy begins with a validated lead target, incorporating the dual payload concept as our innovation. Moving forward, we plan to introduce more novelty and undertake greater risks.

Initially, proving the platform with a commercially sensible validated target is essential. TROP2 meets these criteria for us. Our lead candidate is a dual payload, TROP2-targeting ADC. We feel -- and some clinicians echo this – that Trodelvy and Dato-DXd are not the home runs that Enhertu was. Our ADC recognizes a distinct conformational epitope compared to Trodelvy and Dato-DXd. It's also a bit more proximal to the membrane, which may address the shedding that can occur with TROP2. Today, that asset is in the lead optimization stage, and by the end of the year we plan to be in non-human primates for a non-GLP toxicity study. That data will form the basis of our next financing round, and also kick off our CMC activities and the larger spend that we need to get it into the clinic. Our near-term goal is to get that safety data in non-human primates with our lead TROP2 asset.

Programs two and three are where we intend to highlight our technology. We've invested significant effort in determining the best approach. We are deeply evaluating targets and formats, benefiting from insights gained at AACR. Our next program will likely be a bispecific ADC with a dual payload. Subsequently, we plan to explore a novel or first-in-class target for our third program, ensuring it complements existing options. For example, comparing Claudin 18.2 and Claudin 6, we consider patient overlap. Pursuing Claudin 6 might seem appealing, but differentiation is crucial if Claudin 18.2 or another target serves the same patient population. We're diligently analyzing these aspects, particularly for bi-specific formats, ensuring our targets are appropriate. Programs two and three focus on showcasing our platform with innovative assets, avoiding duplication.

‍

You mentioned Trodelvy and Dato-DXd, and that there is considerable skepticism about their effectiveness as definitive solutions. What are the reasons behind this skepticism, and what insights have you gathered

TROP2 appears to contribute to some of the observed challenges, such as skin toxicity. It remains unclear how much this contributes to the safety issues encountered. ILD continues to be an issue with Dato, which may be due to linker instability. That's why the monkey toxicity study is important: You will see many of the same side effects in non-human primates as in humans. Ocular toxicity can be seen in monkeys, and skin toxicity as well. It’s something to keep an eye out for when looking at TROP2 assets generally, understanding what the skin toxicity profile is, how high they’re able to dose, and things like that.

Taking a broader perspective, Trodelvy does not show significant advantages over traditional chemotherapy due to issues with its linker and stability—these are often cited as reasons why it is not commonly used as a benchmark in in vitro studies. It essentially behaves like free chemotherapy. Thus, Trodelvy has inherent limitations. While Dato-DXd appears more promising than Trodelvy, safety concerns persist. Improving the linker or selecting a better payload could potentially enhance its efficacy, although challenges may persist if TROP2 proves less tractable than HER2. This strategy suggests a promising niche, likely beginning in refractory cases and progressing based on accumulating data.

‍

You also mentioned financing. Your previous round, a seed round, raised $1.5 million. How did that funding support you, when is the next round planned, and what is needed to begin non-human primate studies?

Our initial raise helped get the company off the ground and enabled key hires such as my CSO, Daniel Periera, who worked on Padcev while at Agensys. It also kicked off some of the preclinical work around the lead optimization we wanted to start. And, importantly, it got us started on the licensing, getting all of that situated. The initial funds allowed us to start the company, pressure test the concept, and get some initial data. We have also just received a $2.6 million CPRIT grant, which will help us support the TROP2 ADC lead candidate through the development stage. We’ve also signed a research collaboration with a public pharma company that we hope to announce in the next few months.

In terms of financing today, we’re currently raising $12 million. We've got a lead investor who is committing $5 million with the syndicate completed for the $12M with an oversubscription. What has helped catalyze investor sentiment today has been the continued validation of our lead program and getting non-diluted funding. That was really important. We've had inbounds from multiple interested strategic partners, and we expect to be making announcements soon on that front. Investors have been able to get a view through those conversations, and it’s been really helpful to have folks understand that there is interest today, and there'll be more interest as we build out the technology further. Then, the goal is to kick off our Series A around JPM and close the first half of next year. We've already been having those discussions with the series A investors interested in funding clinical milestones, but we need to have that non-GLP monkey toxicity first to get over the goal line when it comes to writing a check and showing the right risk profile. We've been able to leverage the strategic interests to complete our financing, to build our data then, and to have line-of-sight to a series A round.

‍

Assembling your team seems to have played a crucial role in your success and strategy. Could you provide a recap of who's on the team and how you've approached building out this new company?

As I familiarized myself with ADCs, it quickly became apparent that manufacturing is a prominent challenge. I engaged with leaders in ADC manufacturing and connected with Morris Rosenberg, our acting CTO and consultant with extensive experience at Seagen and as CTO at Immunomedics. His enthusiastic response upon reviewing our technology was incredibly validating. Additionally, I consulted Chris O'Donnell from Pfizer Ventures, a seasoned chemist who worked on ADCs for Pyxis. He shared insights into past struggles with dual payload ADCs, such as linker stability, aggregation, and purification issues. Morris's deep understanding of our technology and its manufacturing advantages has significantly bolstered my confidence. Many venture capitalists we've spoken with rely on Morris for due diligence on manufacturing feasibility. His endorsement during discussions has played a crucial role in easing investor concerns and facilitating productive investment conversations.

 Adding to our team's strength, Abhishake Chhibber joined us, bringing a wealth of experience from BioNTech, where he navigated post-COVID strategy and ADC/cancer vaccine deals. His commercial acumen, honed at AstraZeneca and MedImmune, was instrumental in shaping our investor and clinician engagement strategy. Subsequently, Dan Pereira came on board as CSO, leveraging decades of industry experience and involvement with 5 FDA approvals, including his role in helping to develope Padcev. Dan's expertise in ADCs and biologics enhances our platform's differentiation and execution capabilities.

Our scientific foundation is anchored by co-founders Kyoji Tsuchikama and Zhiqiang An. Kyoji's groundbreaking work in dual-payload ADCs, recognized with awards like Outstanding Academic Investigator of the Year at the World ADC Conference, underscores the strength of our scientific approach. Zhiqiang's extensive tenure at Merck and leadership in antibody development further solidify our scientific credibility, with numerous antibodies licensed and in clinical trials. Bringing together this talented team, aligned by a shared mission, has been pivotal in our success. Each member contributes uniquely, allowing us to leverage our strong scientific foundation and strategic vision effectively.

‍

Exciting! What should the community be on the lookout for in the coming year?

We’re not looking to be a “me-too,” or a fast follower. We are very excited about the upcoming monkey data, which will allow our race to start officially. We are very thoughtful about how we de-risk the platform and showcase what a dual payload system could do by leveraging exciting concepts on the payload side and the targeting and format side. We hope this will create better assets that will transform patient outcomes.

This has been an interesting conversation, and we're excited about the ADC innovation, the Texas Life Science ecosystem, and the work you are doing at CrossBridge Bio. We will keep an eye on any deals and progress in the coming months and years and look forward to talking again soon.

‍