Advancing Immuno-Oncology: The CytomX Story

An interview with Sean McCarthy, President & CEO, CytomX Therapeutics.

CytomX Therapeutics, an oncology-focused biotech company based in San Francisco, CA, develops a novel class of antibody therapeutics based on its Probody technology platform. Probody therapeutics are designed to exploit unique conditions of the tumor microenvironment to more effectively localize antibody binding and activity while limiting activity in healthy tissues. The company’s pipeline includes potentially best in class cancer immunotherapies against clinically-validated targets, such as PD-L1 and CTLA-4, and first-in-class Probody drug conjugates against highly attractive targets, such as CD166 and CD71, which are considered to be inaccessible to conventional antibody drug conjugates due to their presence on healthy tissue.

Launched ten years ago from technology development at the University of Santa Barbara, California, CytomX has grown rapidly in recent years from a research-intensive startup to a R&D company, boasting key strategic partnerships with big pharma companies such as Bristol-Myers Squibb (BMS), AbbVie, and Pfizer. In October 2017, the company’s stock rose 35% after it announced its newest partnership with Amgen.

Sean McCarthy, President & CEO, joined CytomX in 2010 when the company was still “very embryonic”. He recently sat down with PharmExec to explain the potential of the Probody platform technology and outline the company’s journey from university startup to rising star of the immuno-oncology space.

PharmExec: What key developments in the oncology space in the last ten years that have helped to facilitate CytomX’s journey?

Sean McCarthy: The biggest development in the oncology field in the last 5–10 years has been the advent of immuno-oncology (IO). The current wave began in 2011 with the approval of BMS’s drug YERVOY (ipilimumab), a therapeutic antibody that blocks CTLA-4. If you block CTLA-4, which is a checkpoint target, you can activate T cells and release a brake on the immune system. Tumor cells are very clever in that they can mimic normal tissue and evade immune surveillance, but what James Allison and colleagues realized was that if you could re-awaken the immune system by blocking checkpoint targets, you could then motivate the immune system to recognize cancer and eliminate it. YERVOY was a real breakthrough drug, particularly in the field of melanoma, and since then there has been a tsunami of innovation in IO, leading to the approval of many drugs against a number of other checkpoint targets and a dramatic advance in how we think about the treatment of cancer.

There are two challenges with these class of drugs. First, when you release the “brake” to motivate the immune system to recognize cancer, you activate the immune system throughout the patient’s entire body, and that causes a whole new set of very severe side effects as the immune system attacks and destroys many different tissues in a fairly random and unpredictable way. Second, most patients do not respond to these new drugs; of those who do, most ultimately relapse, so we still need better drugs. The second challenge is that, with immunotherapy,

Looking at cancer research and thinking about how to develop the next wave of innovative medicines led us at CytomX to try and make more effective immunotherapies that are (a) locally effective in the tumor and avoid systemic activation of the patient’s immune system and (b) more active drugs that are able to treat patients who are not responding to immunotherapy or patients who relapse on immunotherapy. We’re developing what we call Probodies. Probodies are therapeutic antibodies that have been engineered to be active within tumor tissue but not in normal tissue, thus sparing the systemic autoimmune side effects. We put what a “mask” onto the therapeutic antibody, which impairs the ability of the antibody to bind to its target until the mask is removed.  The mask can be removed locallyin cancer tissue by a class of proteins called proteases, which are highly active in tumors but generally inert systemically. Our Probody platform has the potential to focus the activity of cancer immunotherapies to the tumor microenvironment. In addition, we also have the opportunity to go after a whole new set of targets that have not been addressed before by the industry, because they are present on tumor tissue at very high levels but also present on normal tissue. For these types of targets, we conjugate the Probody to a cytotoxic cell killing payload and make these molecules highly active and highly potent, but only in the tumor. This class of drugs we call Probody drug conjugates.

How did you tackle the early challenges of surviving in this competitive space?

Our Probody technology came out of University of California, Santa Barbara, about ten years ago and the idea was good enough that the founders of the company were able to raise a few million dollars of angel financing in the Santa Barbara community to open a small lab and do some initial experiments. That initial research allowed the first venture capital financing of the company, led by Boston’s Third Rock Ventures, to take place in September 2010. We then set about building a team of about 25 researchers to really interrogate the technology and generate initial preclinical proof of concept, which we achieved in 2011–2012. That allowed us to secure our first partnership with a large pharma company, Pfizer, in 2013. By 2014, IO was really picking up steam.  Around this time,  researchers at Stanford Universityshowed that the administration of checkpoint inhibitors directly into cancer tissue could elicit an anti-cancerous response, suggesting for the first time that, for these immunotherapies, you might not need to activate the immune system throughout the patient’s body to elicit an anti-tumor response. That’s exactly what Probodies are designed to do. We then began talking to BMS, the company that launched YERVOY, and we were able to strike a major partnership with them in 2014. That was a major inflection point for us, it put us on the IO map, and within a year or so we were a public company traded on NASDAQ.

We’re already beginning to see tangible results from our partnership with BMS. We recently announced the FDA acceptance of our Investigational New Drug application for a CTLA-4 Probody therapeutic. CTLA-4, the clinically validated target of YERVOY, is the first target to advance into the clinic under our strategic partnership and a validation that our innovative approach to IO has potential

One of the fundamental aspects of this company is the innovation and disruption inherent in our technology. There’s often a point in investor meetings where there is a brief silence and then someone will say, “You know what? That is a really good idea!” In the early days of CytomX, we really focused on reducing that idea to practice and pressure-test the technology in a lot of different ways. We were then able to strike significant partnerships with leading pharmaceutical companies and raise capital from high quality private and public investors.  In more recent days, we’ve take multiple Probodies into clinical studies and evolved into a clinical stage company. 

A startup can define its own culture but this can be compromised as it grows more successful. Is this a fear for CytomX?

It something we talk about all the time and have done so since the earliest says of the company. We’ve been through an evolution over the last couple of years from being very a research-intensive, science-driven company to a being a research and development company, one that is more product-development oriented. But we retain the principles that have guided us from the early days. We sat down as a small team years ago and developed our vision statement, “Transforming lives with safer, more effective therapies”, and that is something we think about every day. It speaks to our desire to urgently advance a pipeline of innovative Probody therapeutics into the clinic. Our core values are integrity, commitment, creativity, accountability, and fun. We enjoy working together and we celebrate our success. We really emphasize leadership and not just technical, functional, transactional leadership-we expect our leaders to have all those qualities. We also expect our leaders to be transformational leaders, who really think about their people, how they develop them, how they are feeling. As the company grows it can be very difficult to maintain a culture, so we are very focused on nurturing this cultural foundation we have built.

What is the 5–10-year outlook for CytomX?

If we wind the clock back to 2011–2012, when the public market was not available to biotech companies, we weren’t sure what the opportunities for this company were going to be in terms of getting to that market. But we laid out our ambition to build a long-term, multiproduct, commercial-stage oncology company. And we really have a shot now at building that commercial enterprise. So, our 5 to 10-year vision is the same as it was back then, which is to build that company. The roadmap is there-we know the path we need to follow.

Sean McCarthy

cytomx.com/