The story of Q32 Bio, a company that develops therapeutics for inflammatory and autoimmune diseases, started two decades ago. That’s when V. Michael Holers, MD, a University of Colorado School of Medicine professor with a focus on autoimmune diseases; Joshua Thurman, MD, a CU School of Medicine nephrologist; and Medical University of South Carolina immunologist Stephen Tomlinson, PhD, started collaborating.
CU Innovations has partnered with Q32 Bio since the company’s founding in 2017, and its venture arm has also invested in the company. Considering what Q32 Bio has accomplished – and, more poignantly for patients, its tantalizing potential – it’s easy to see why. Should Q32 Bio’s drug candidates pan out, it could provide a skeleton key for therapeutics targeting a dizzying array of autoimmune and inflammatory diseases.
Most recently, on Nov. 16, 2023, Q32 Bio, Inc., announced its reverse merger with Homology Medicines, Inc., a publicly listed biotech. The combined company will assume the Q32 Bio name and, with help from an additional $42 million cash infusion from several investors, continue to advance Q32 Bio’s two autoimmune and inflammatory therapeutic candidates.
One cascade, many maladies
Holers, currently the director of faculty ventures at CU Innovations, was already a preeminent expert in the complement system, a part of the innate immune system so evolutionarily ancient it’s found in fish, reptiles and horseshoe crabs. The complement system involves a cascade of more than 40 proteins floating about in the blood plasma and on cell surfaces that, when operating optimally, tag and help destroy pathogens and diseased cells. Its fundamental job, Holers says, “is to protect ‘self’ from ‘non-self.’”
Holers recalls that, back when he was a CU rheumatology fellow in the early 1980s, the complement system was thought to be “a really elegant, but essentially irrelevant, part of the immune system.” The intervening decades – and, to no small degree, Holers himself – have proven that wrong.
“The right tissue-targeting strategy could become many different drugs for many different diseases.”
– Joshua Thurman, MD
We now know that the complement system, despite its eons of experience, makes rookie mistakes by attacking, rather than protecting, “self.” Over time, that can cause a variety of autoimmune diseases and trigger inflammation that exacerbates other diseases, disorders and injuries. The complement system is complicit in cardiovascular diseases, cancer, age-related neurodegenerative diseases and kidney diseases, among many others, in addition to transplant-organ rejection.
Given all that, keeping the complement system in check has become a serious pharmaceutical focus. The therapies emerging from these efforts target different proteins along the complement system’s cascade of biochemical reactions, but they have one thing in common: They go after those proteins while they’re floating in the bloodstream. That’s not ideal for two main reasons.
The first has to do with bioavailability. Blood plasma is rich in complement proteins – oft-targeted C3 alone accounts for more than 0.1% of plasma volume – meaning it takes a lot of drug to bind with it all. Further, the complement cascade involves reactions that constantly turn C3 into C3a and C3b fragments and on down the line, so C3’s serum half-life ranges from hours to days, max, and that’s true for plasma proteins throughout the cascade.
Second, the complement system exists in every vertebrate for a reason. It plays a critical role in fighting infections and shaping adaptive immune responses, among other actions. That applies to those whose complement systems are causing health problems. Systemically impeding the complement system introduces immunological risk.
To the cellular surface
A decade ago, Holers, Thurman and Tomlinson were not alone in recognizing that the ideal solution would be to regulate the complement system not systemically in blood plasma, but rather on the surfaces of cells the complement system unjustly attacks (technically called tissue-directed complement therapeutics). They were among the few, however, with the skills and capacity to act on that recognition, and the persistence to test different strategies and work through various potential roadblocks along the way.
The optimal cell-surface complement-protein targeting would happen through a lab-designed monoclonal antibody that, like one created by the immune system itself, would bind to a particular protein. That monoclonal antibody would carry a payload of custom proteins that would interfere with other complement proteins in the unfolding cascade on the cellular surface.
That introduced two big research questions: What exactly is on a cell’s surface to target? And, once you landed these bespoke monoclonal antibodies on the surfaces of cells, what part of the complement cascade would they interfere with? The team would then have to prove it worked and that, by working, the approach might bring therapeutic benefit.
Doing so took years of lab work involving recombinant molecular biology, structure studies using X-ray crystallography and other tools, mouse models, patient samples for in-vitro testing, and much more. There were dead ends. In particular, Thurman says, the team first designed the monoclonal antibody to target proteins recognized as injury markers on cells, and that ran into technical roadblocks. Then they came upon C3d.
C3d bound tight
C3d is a complement protein that, once activated, binds covalently to tissues in great numbers, thereby marking cells for immunological attack. That sort of irreversible covalent bonding is “incredibly rare” for a protein whose immediate precursors float around in plasma, Holers says.
Beyond C3d’s permanence, which would address the bioavailability problems facing systemic complement drugs, C3d proteins change shape slightly once affixed to cells, so a monoclonal antibody could target cell-surface C3d and not be sopped up by the proteins crowding the bloodstream. Also, C3d binds only when the complement system is active on a cell’s surface, and it’s scattered among C3 convertase complexes that trigger a cascade of immune action, including the creation of cell-membrane-penetrating membrane attack complexes (MACs).
Taken together, Holers says, an approach targeting C3d on cell surfaces “is a really nice conjunction of fundamental biology, biochemistry, and therapeutic strategies to direct inhibitors of a pathway specifically to a site where the pathway is activated.”
In 2017, the team tapped CU Innovations to help launch AdMIRx, soon to be renamed Q32 Bio, to do the hard work of turning their research results into a viable drug candidate, ADX-097. Holers, who had previously launched Taligen with CU Innovations help, was familiar with the CU Anschutz-based operation’s expertise in intellectual property, patents, investor outreach and relationship development. Early on, CU Innovations helped the startup land funding with the CU Chancellor’s Discovery and Innovation Fund as well as a Colorado Office of Economic Development and International Trade – Advanced Industry Accelerator (OEDIT AIA) grant.
“CU Innovations really shored up those aspects, because that’s where we, as academic investigators, really need help to launch our ideas,” Thurman says.
It has taken 30 years of research by teams around the world for that “essentially irrelevant” complement immune system to become what Holers describes as “one of the most important therapeutic targets in all of biology.”
Q32 Bio’s ADX-097 has completed a Phase 1 clinical trial involving healthy volunteers, and the company says it is planning Phase 2 clinical trials in which ADX-097 will target renal diseases and ANCA-associated vasculitis (AAV).
But Q32 Bio’s greatest promise may lie in developing the antibody co-developed in Holers’ and Thurman’s labs as a platform – a “backbone targeting technique,” as Thurman describes it. Part of the challenge, Holers and Thurman agree, will be choosing where to apply that platform first when the complement system is activated “in essentially all human diseases,” Holers says. The founding scientists themselves have their favorites. Thurman the nephrologist treats kidney disease; Holers is a rheumatologist; and Tomlinson has an interest in neurological conditions.
Ideally, they’ll all get their medicines.
“The right tissue-targeting strategy could become many different drugs for many different diseases,” Thurman says.
Guest contributor: Todd Neff; photo at top: V. Michael Holers, MD, and Joshua Thurman, MD.
