The tracer at the center of the study, known as [68Ga]Ga-ATH001, is an Affibody molecule, a small engineered protein scaffold roughly a tenth the size of an antibody, that binds with picomolar affinity to platelet-derived growth factor receptor beta, or PDGFRβ. This receptor is a well-established hallmark of activated pericytes and, critically, of activated hepatic stellate cells, the liver-resident cells that transform into collagen-producing factories during fibrogenesis. Because PDGFRβ is upregulated on the cells actively driving extracellular matrix deposition across the liver, lung, heart and tumor stroma, it offers a molecular handle for imaging not the aftermath of scarring but the scarring process itself, while it is still underway and still treatable.

Before any new radiotracer can be used diagnostically, regulators and clinicians need to know exactly where it goes in the body and how much radiation it deposits along the way. That is the question the research team, led by Mark Lubberink of Uppsala University together with colleagues from Karolinska Institutet, Antaros Medical, Antaros Tracer and Takeda Development Center Americas, set out to answer in a first-in-human study registered as NCT06562361. The dosimetry cohort comprised six participants: three healthy volunteers, all 22 years old, and three patients with metabolic dysfunction-associated steatohepatitis, or MASH, the aggressive form of fatty liver disease in which fibrosis is a central driver of disease progression and mortality.

Each participant received an intravenous bolus of approximately 2.5 megabecquerels per kilogram of body weight of the gallium-68-labeled tracer, corresponding to an average injected activity of 178 MBq and a peptide mass of just 51 micrograms, roughly a thousandth of a drop of protein. Imaging began immediately, with a dynamic PET/MRI scan over the abdomen capturing the first 35 minutes of tracer distribution in real time, followed by whole-body PET scans at one, two and three hours after injection. In total, 25 organs and tissues were segmented and analyzed, from the liver, kidneys and spleen to the red bone marrow, salivary glands, thyroid and gonads, providing an unusually comprehensive map of the tracer’s journey through the body.

The biodistribution results told a clean and encouraging story. The tracer spread rapidly through the circulation and then cleared quickly from most tissues, so that by two hours after injection, radioactivity remained essentially only in the kidneys and bladder, the sole route of excretion, and in the spleen, which naturally expresses abundant PDGFRβ. In the healthy volunteers, liver uptake had already fallen close to background levels. In the MASH patients, by contrast, liver uptake was significantly higher, with a standardized uptake value of 4.0 compared with 2.8 in the healthy group, a difference the authors attribute to the upregulation of PDGFRβ on activated hepatic stellate cells engaged in ongoing fibrogenesis. In other words, the tracer did exactly what it was designed to do: distinguish fibrotically active livers from quiescent ones.

On the radiation side, the calculations, performed with the IDAC DOSE 2.1 software using the ICRP 103 framework and ICRP 110 reference phantoms scaled to each participant’s body weight, yielded a sex-averaged effective dose of 0.028 ± 0.002 millisieverts per megabecquerel. The kidneys emerged as the dose-limiting organ, absorbing 0.34 mGy/MBq in males and 0.46 mGy/MBq in females, a consequence of the renal tubules reabsorbing the peptide-based tracer and trapping the gallium-68 intracellularly, a well-known behavior of this class of small radiolabeled proteins. At the clinically targeted activity of 2 MBq per kilogram, roughly 150 MBq for a typical adult male, the total effective dose would come to 4.1 mSv, with kidney absorbed doses of about 50 mGy in males and 55 mGy in females.

Those numbers place [68Ga]Ga-ATH001 in familiar company. Its effective dose is comparable to other gallium-68-labeled Affibody molecules previously evaluated in humans and only slightly higher than that of established peptide tracers such as [68Ga]Ga-DOTATOC, used routinely in neuroendocrine tumor imaging, or the workhorse PET radiopharmaceutical fluorodeoxyglucose. Given that a single abdominal CT scan can deliver an effective dose in the range of 10 mSv, a 4.1 mSv PET study that can be repeated over months or years represents a radiation profile compatible with the longitudinal study designs that fibrosis research desperately needs, subject of course to applicable regulatory and ethical requirements.

Safety was equally reassuring. Participants were monitored for up to 24 hours after dosing with laboratory assessments, vital signs and electrocardiography, and none experienced any adverse effects following administration of up to 70 micrograms of the precursor peptide, approximately 0.9 micrograms per kilogram. The authors also carefully catalogued the uncertainties in their dosimetry, noting that the scan protocol, with its 35-minute dynamic acquisition followed by serial whole-body imaging, kept the extrapolated fraction of the time-integrated activity below 20 percent for most organs in the dynamic field of view, and that the bladder dose estimate, based solely on PET data without assuming voiding, likely overestimates the true absorbed dose.

The significance of this work extends well beyond liver disease. Because PDGFRβ activity is entwined with angiogenesis, tissue remodeling and wound healing throughout the body, a validated PET marker of the receptor opens the door to non-invasive monitoring of fibrogenesis in the lung, the heart, where a separate trial in myocardial infarction patients is already underway, and the tumor microenvironment. For MASH in particular, where novel anti-fibrotic drugs are flooding the pipeline and patient stratification remains a major bottleneck, a tracer that quantifies active fibrogenesis could transform how patients are selected for trials and how treatment response is measured, replacing repeated biopsies with a one-hour scan.

Much work remains before [68Ga]Ga-ATH001 reaches routine clinical use. The dosimetry cohort was small, and liver uptake will be explored further in additional participants across different stages of MASH within the ongoing clinical study. Still, the combination of favorable dosimetry, clean safety data and demonstrable discrimination between healthy and fibrotically active livers gives the tracer a strong foundation for the next phase of development. If subsequent studies confirm its diagnostic accuracy, clinicians may soon gain what they have lacked for decades: a repeatable, quantitative window into the scarring process itself, caught early enough to do something about it.

Subject of Research: First-in-human biodistribution and radiation dosimetry of the PDGFRβ-targeting PET tracer [68Ga]Ga-ATH001 for imaging active fibrosis

Article Title: Biodistribution and radiation dosimetry of the PDGFRβ targeting PET tracer [68Ga]Ga-ATH001

Article References: Lubberink, M., Lohith, T. G., Derdak, Z., Wilkens, P., Palmér, E., Ramolli, A., Ferrat, M., Tran, T. A., Mitran, B., Abouyzayed, A., Johansson, L., Wennbo, H., Rorsman, F., Vessby, J., & Eriksson, O. (2026). Biodistribution and radiation dosimetry of the PDGFRβ targeting PET tracer [68Ga]Ga-ATH001. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08167-9

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08167-9

Keywords: PET imaging, PDGFRβ, fibrosis, radiation dosimetry, Affibody molecule, gallium-68, MASH, liver fibrogenesis, hepatic stellate cells, first-in-human study, molecular imaging, radiotracer safety

Gout is one of the most common inflammatory joint diseases worldwide, driven by chronically elevated levels of urate in the blood. When urate crystallizes in joints and soft tissues, it triggers excruciating attacks of arthritis and, over time, can produce tophi, the disfiguring deposits of urate crystals that characterize advanced disease. Most patients are managed with oral medications such as allopurinol or febuxostat, which reduce urate production, or uricosuric agents that increase its excretion through the kidneys. But a substantial minority of patients cannot reach target urate levels with these drugs, cannot tolerate them, or carry contraindications such as severe kidney impairment. For these individuals, guidelines in China, Europe, and elsewhere recognize an alternative approach: replacing the enzyme that humans lack.

Humans, unlike most other mammals, do not possess functional uricase, the enzyme that converts uric acid into the far more soluble compound allantoin, which is readily excreted by the kidneys. This evolutionary loss of uricase is thought to have been advantageous in our primate ancestors, possibly because uric acid acts as an antioxidant and may have helped maintain blood pressure on ancient low-salt diets. The trade-off is that humans are uniquely vulnerable to hyperuricemia. Recombinant uricase therapy restores the missing enzymatic activity pharmacologically. Rasburicase, a non-PEGylated uricase, is already used to prevent tumor lysis syndrome in oncology, while pegloticase, a PEGylated mammalian uricase, is approved for chronic refractory gout. PEGylation, the attachment of polyethylene glycol chains to a protein, extends the drug’s half-life and shields it from rapid immune clearance, but it also introduces its own immunological complications, since many people carry pre-existing antibodies against polyethylene glycol itself.

HZBio1, developed by Hangzhou Grand Biologic Pharmaceutical, is a PEGylated recombinant uricase produced in Escherichia coli. Each active enzyme molecule is a homotetramer, a four-subunit assembly in which every monomer consists of 298 amino acids. Lysine residues on the surface of the tetramer serve as convenient attachment points for polyethylene glycol modification, allowing the drug to be manufactured with a consistent architecture. The design goal is familiar to anyone following the biologics field: retain the catalytic power of the bacterial enzyme while disguising it long enough to circulate and work, and ideally with less immunogenicity than existing PEGylated uricases.

To test that concept, investigators at Peking Union Medical College Hospital in Beijing enrolled 40 healthy volunteers aged 18 to 45 years between March 2021 and January 2022. Thirty participants were randomly assigned to five dose-escalation cohorts of six subjects each, while ten received placebo. Every subject received a single intramuscular injection of either HZBio1, at doses ranging from 0.96 to 12 milligrams, or placebo. The trial was registered with ClinicalTrials.gov under identifier NCT04765995 and approved by the hospital’s ethics committee for drug clinical trials, and all participants provided written informed consent. The study followed each subject for 35 days after dosing, tracking safety, drug concentrations in plasma, uric acid dynamics, and antibody responses.

The safety picture was reassuring, if not entirely free of signals. Treatment-emergent adverse events occurred in 76.7 percent of HZBio1 recipients compared with 60.0 percent of placebo recipients, a gap that reflects the background noise of minor complaints common in any phase 1 population. Drug-related adverse events were reported in 73.3 percent of the active group versus 60.0 percent on placebo. Critically, every adverse event recorded during the follow-up period was grade 1 or grade 2 in severity, meaning mild to moderate, and the vast majority were described as mild and self-limiting. No severe events, dose-limiting toxicities, or safety signals requiring discontinuation emerged across the dose range explored.

The pharmacokinetic data revealed an intriguing property. Across the 3- to 12-milligram range, systemic exposure to HZBio1 increased in a greater than dose-proportional manner, meaning that doubling the dose more than doubled the drug’s presence in the bloodstream. Such super-proportional exposure can occur when a drug’s absorption or clearance pathways become saturated, and it has practical implications for dosing, since small increments in dose may produce disproportionately large changes in exposure. For a first-in-human program, characterizing this nonlinearity early is exactly what dose-escalation studies are designed to accomplish, and it will inform how future trials select and space doses.

The pharmacodynamic results were the trial’s headline attraction. A single injection of HZBio1 sent plasma uric acid concentrations falling, with levels reaching their nadir between 144 and 192 hours after dosing, roughly six to eight days. The reduction was most pronounced in the 9- and 12-milligram cohorts, and among subjects receiving 6 to 12 milligrams, participants achieved at least a 50 percent reduction in plasma urate over the 35-day observation period. A urate-lowering effect of that magnitude and duration, from a single intramuscular dose, is notable because it suggests the PEGylated enzyme remains active in circulation for an extended period, potentially allowing an infrequent dosing schedule that would be attractive for a chronic disease like gout.

Immunogenicity, the perennial concern with PEGylated proteins, was monitored with equal care. HZBio1 administration elicited low-titer antibodies against polyethylene glycol, of both the immunoglobulin G and immunoglobulin M classes. By contrast, antibodies directed against the drug protein itself were rarely detected, and no subject developed neutralizing antibodies, the kind that would inactivate the enzyme and potentially blunt or abolish its therapeutic effect. The distinction matters because neutralizing antidrug antibodies are the principal reason some patients lose response to pegloticase, and pre-existing or induced anti-PEG antibodies have been linked to infusion reactions with other PEGylated medicines. Whether the low-titer anti-PEG response observed here remains clinically silent with repeated dosing is a question only longer studies can answer.

The authors conclude that HZBio1 at doses of 3 to 12 milligrams was well tolerated in healthy subjects, showed an acceptable pharmacokinetic profile, and produced a promising urate-lowering effect. The trial was funded by Hangzhou Grand Biologic Pharmaceutical, with the funder reporting no role in the design, conduct, analysis, or reporting of the research; two authors are company employees and one is employed by Grand Life Sciences Group, while the academic investigators disclosed no conflicts of interest. As with any phase 1a study, the caveats are substantial: only 40 subjects were involved, all were young and healthy Chinese adults rather than patients with gout, and each received just one dose. The super-proportional exposure seen at higher doses will need careful management in patient trials, and the durability of the immune response under repeated administration remains untested. Nevertheless, the combination of mild adverse events, sustained urate suppression, and an apparently favorable antibody profile gives HZBio1 a credible foundation for advancing into phase 1b and phase 2 studies in the hyperuricemic and gout populations who most need a new enzymatic option.

Subject of Research: First-in-human phase 1a evaluation of the PEGylated recombinant uricase HZBio1 for hyperuricemia and gout

Article Title: Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of HZBio1 in Chinese Healthy Subjects: A Randomized Phase 1a Study

Article References: Liu, H., Zheng, X., Yang, C., Tian, W., Wan, R., Wang, Y., Yu, Y., Wang, Q., & Wang, H. (2026). Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of HZBio1 in Chinese Healthy Subjects: A Randomized Phase 1a Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03792-0

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03792-0

Keywords: HZBio1, PEGylated uricase, gout, hyperuricemia, phase 1a trial, pharmacokinetics, pharmacodynamics, immunogenicity, anti-PEG antibodies, urate-lowering therapy, biologics, first-in-human study