Fredrik Frejd, Chief Scientific Officer at Affibody, explains how the company’s radiotherapeutic candidate could address some of the limitations inherent in current approaches.
The field of targeted radiopharmaceuticals has witnessed remarkable growth in recent years, driven by blockbuster successes of Novartis’ Lutathera (lutetium Lu 177 dotatate) and Pluvicto (lutetium Lu 177 vipivotide tetraxetan), which together generated over $2 billion in sales in 2024.
This commercial validation has sparked intense interest from both pharmaceutical companies and investors, with multiple billion-dollar acquisitions in the radiopharmaceutical space signalling confidence in the therapeutic approach.
Acceleration of Phase I study with ABY-271 following initial patient data
In October 2025, Affibody announced that the first patient had been dosed in a Phase I clinical study evaluating ABY-271, a lutetium-177-labeled radiotherapeutic targeting HER2-positive cancer. The Phase I study is an open-label, two-stage, randomised trial designed to assess the safety, tolerability and biodistribution of ABY-271 in subjects with HER2-positive metastatic breast cancer. The trial is being conducted at sites specialised in breast cancer and nuclear medicine in Sweden and Germany.
The study comprises two distinct parts. Part A will evaluate the uptake of ABY-271 in tumours and critical organs in up to six sequentially enrolled patients, while Part B will evaluate higher radioactivity levels and additional protein dose range for subsequent clinical trials in a total of 15 randomised patients. Patients in both parts will receive a single intravenous infusion of ABY-271. Oscar Wiklander at Karolinska University Hospital serves as the coordinating investigator in Sweden. In December 2025, promising initial results from the first cohort of patients was announced demonstrating tumour targeting and a favourable safety profile with low uptake in kidneys and other critical organs. Based on the positive data, the Trial Review Committee recommended to advance the study to its second part, where higher radioactivity levels will be evaluated. In line with this recommendation, Affibody has submitted a protocol amendment to the European Medicines Agency (EMA) to accelerate the transition to the second part, which is expected to start in H1 2026.
Affibody molecules
At the heart of Affibody’s approach lies a proprietary technology platform that represents a departure from conventional antibody-based therapeutics. Affibody molecules are a novel drug class of small therapeutic proteins with characteristics that may offer substantial advantages over monoclonal antibodies (mAbs), antibody fragments and small peptides. These molecules are derived from a robust three-helical protein scaffold, known to have remarkable stability that allows combinatorial protein engineering to bind specific target proteins with high affinity and specificity.
The size difference is particularly striking: at approximately 6kDa, Affibody molecules are roughly 20 times smaller than full-length monoclonal antibodies (150kDa) and around 20 times larger than small molecules. Affibody molecules can deliver the specificity of a monoclonal antibody and the flexibility of a smaller molecule. The company has created a large library consisting of more than ten billion Affibody molecules, all with unique binding sites, from which binders to given targets are selected. This optimal size, combined with a stable three-helix bundle structure, confers several important pharmacological properties that are especially relevant for radiopharmaceutical applications.
For radiotherapy applications, the biodistribution profile is critical. The agent must penetrate tumours efficiently, clear rapidly from non-target tissues to minimise radiation exposure yet remain in the tumour long enough for the radioisotope to exert its therapeutic effect. Through addition of the proprietary albumin-binding domain Albumod, the biodistribution of Affibody molecules can be tuned for radiotherapy applications enabling high tumour uptake and penetration, combined with low kidney and liver accumulation and minimal bone marrow exposure.
Engineering ABY-271
ABY-271’s development builds directly on clinical insights gained from Affibody’s diagnostic PET imaging agent, tezatabep matraxetan (ABY-025), showing that the candidate substance can detect HER2 independently of the tumour origin. This PET analogue has demonstrated clinical utility in Phase II trials, successfully visualising HER2-expressing cancer lesions throughout the body including in patients with low HER2 expression and demonstrated ability to predict response to HER2-target treatment.
Through protein engineering, molecular formatting, and addition of the proprietary albumin-binding domain Albumod, the HER2 targeting sequence of tezatabep matraxetan was optimised for therapeutic biodistribution properties and developed into the therapeutic candidate ABY-271. The addition of the albumin-binding domain is particularly clever from a pharmacokinetic perspective. Albumin is known as a unique molecule, having good transportation properties with high extravasation rate and very good exposure in tissues and tumour lesions. By binding to albumin in circulation, ABY-271 achieves a half-life that allows for optimal tumour accumulation while still maintaining relatively rapid clearance from blood and normal tissues. Radiolabeling with lutetium-177 via a DOTA chelator creates the therapeutic radioligand [177Lu]Lu-ABY-271. Lutetium-177 emits beta radiation with a mean tissue penetration range of approximately 0.7mm, making it well-suited for delivering cytotoxic radiation to tumour cells while minimising damage to surrounding healthy tissue.
Importantly, the theranostic ABY-025/ABY-271 pair targets a different HER2 epitope compared to trastuzumab or pertuzumab or their ADC derivatives, allowing them to be administered concomitantly. This non-overlapping binding site opens the possibility for combination therapy approaches that could enhance clinical benefit.
Compelling preclinical evidence
The preclinical development programme for ABY-271 has been comprehensive, generating data that supported regulatory approval to proceed to human studies. Preclinical utility and efficacy of [177Lu]Lu-ABY-271 were analysed in biodistribution and therapy studies in a murine xenograft model.
In biodistribution studies using mice bearing HER2-expressing SKOV-3 xenografts, [177Lu]Lu-ABY-271 demonstrated a beneficial biodistribution profile, with a balanced blood and kidney clearance and accumulation in tumours that exceeded uptake in all other organs by the 24-hour timepoint. This favourable biodistribution is critical, as it suggests that therapeutic radiation doses can be delivered to tumours while minimising exposure to dose-limiting organs such as the kidneys and bone marrow.
The therapeutic efficacy studies were particularly encouraging. Median survival of xenograft-bearing mice receiving a single dose of 21 MBq [177Lu]Lu-ABY-271 was significantly longer than that of mice receiving vehicle control or trastuzumab, while combination treatment of [177Lu]Lu-ABY-271 and trastuzumab further increased the number of complete tumour remissions. The ability to achieve complete remissions in a preclinical model, particularly when combined with standard HER2-targeted therapy, suggests meaningful therapeutic potential.
Safety evaluation is paramount for any radiotherapeutic. Histopathological evaluation of liver and kidney in the therapy study showed only mild changes following [177Lu]Lu-ABY-271 treatment. Further, the GLP toxicity study in rats demonstrated a beneficial safety profile of ABY-271. These findings supported progression into first-in-human trials.
Human dosimetry estimates based on preclinical results predict that tumour doses in the range of approved therapeutic radioligands can be achieved. This is a crucial benchmark, as it suggests that ABY-271 could deliver clinically meaningful radiation doses to tumours comparable to those achieved by Lutathera and Pluvicto.
Building a theranostics ecosystem
Affibody’s development strategy exemplifies the theranostics paradigm, the integration of diagnostic and therapeutic agents targeting the same molecular marker. The theranostic pair consists of the diagnostic agent tezatabep matraxetan, a DOTA-conjugated HER2-binding Affibody molecule developed for whole body molecular imaging of HER2 expression in cancer lesions and ABY-271 for therapy. Affibody is part of building a theranostics trial network to further the theranostics ecosystem. Starting in Sweden and Scandinavia, it is now expanding in Europe and in the USA.
The diagnostic agent has already demonstrated clinical value. In a Phase II study with 50 metastatic breast cancer patients, [68Ga]Ga-ABY-025 PET imaging was predictive for metabolic response to therapy assessed by [18F]FDG PET. This ability to predict treatment response could prove invaluable for patient selection in future ABY-271 studies and, ultimately, clinical practice.
Perhaps even more importantly, tezatabep matraxetan can identify disease heterogeneity that biopsy-based assessment might miss. PET imaging with ABY-025 reveals known disease heterogeneity and identifies limitations of biopsy-based HER2-staging, including in a pilot cohort of 10 breast cancer patients with tumours expressing low levels of HER2 (HER2-low cohort). This whole-body assessment capability could help identify all HER2-expressing lesions that might benefit from ABY-271 treatment, including those that might be missed by sampling a single metastatic site.
A differentiated approach in a crowded field
The radiopharmaceutical space has become increasingly competitive. However, the optimised format of Affibody molecules enables rapid tumour accumulation and tuned blood clearance, both desirable properties for therapeutic applications. The compact structure also allows for more straightforward manufacturing compared to full-length antibodies, potentially translating to more favourable production economics.
The albumin-binding domain represents an elegant solution to the half-life challenge. Rather than relying on Fc-mediated recycling (as antibodies do) or PEGylation (which can be immunogenic), reversible albumin binding provides a “built-in” half-life extension mechanism using an endogenous protein carrier known to have wide distribution and good exposure to tumours. This approach has been validated in other therapeutic contexts but remains relatively underutilised in radiopharmaceuticals.
The non-overlapping epitope on HER2 is another differentiating factor. As patients with HER2-positive cancers increasingly receive multiple lines of HER2-targeted therapy, the ability to add a radiotherapeutic without displacing existing treatments could provide strategic advantages in clinical development and eventual market positioning.
Looking ahead
As the Phase I therapy trial progresses, several key questions will be addressed. The dose-ranging design will help identify the optimal protein mass dose for tumour uptake while minimising uptake in normal tissues. The biodistribution data will validate the preclinical predictions about favourable tumour targeting and normal tissue clearance in human patients. Safety and tolerability assessments will determine the therapeutic window and inform dose selection for potential efficacy trials.
The entry of ABY-271 into clinical development represents more than just another radiotherapeutic candidate, it validates an alternative molecular platform for targeted radiotherapy. If the clinical data support the promise suggested by preclinical studies, Affibody molecules could offer meaningful advantages in tumour penetration, normal tissue clearance and manufacturing efficiency.
For patients with HER2-positive metastatic breast cancer who have exhausted other treatment options, ABY-271 may offer new hope. For the field of radiopharmaceuticals, it demonstrates that innovation in targeting moieties remains a fertile area for improving therapeutic outcomes.
About the author
Fredrik Frejd is Chief Scientific Officer of Affibody AB. He has over 20 years of experience in biomedical research with expertise in tumour biology, biotechnological phage display, and therapeutic protein technique with antibody fragments, as well as artificial scaffold proteins. Frejd is an adjunct Professor at the Department of Cancer Precision Medicine at Uppsala University. He is a Board Director of Mergus development, Akiram Therapeutics, Immuneed, and Deputy Board Director of Amylonix.
