INTRODUCTION

Radiopharmaceuticals are therapeutic compounds that con­tain a radioactive isotope used for the diagnosis, imaging, or treatment of diseases. The role of radiotherapy in precision on­cology is already well established in tumor types, such as prostate cancer and neuroendocrine tumors. There are now emerging studies on the application of radiopharma in other cancer types, including metastatic breast cancer.

Following initial attempts to address radiopharma using full-size monoclonal antibodies (mAbs), recent advances in the ra­diopharma field have predominantly focused on peptides. These significantly smaller molecules can penetrate deep into solid tu­mors and allow more efficient internalization into cells. They also offer lower immunogenicity, easier chemical modification, speed­ier diagnostics, and changed non-target toxicity.

However, with these advances have come challenges, such as difficulty generating potent binders to a broader range of tar­gets and the rapid excretion rate that requires very high amounts of radioactivity to be used since most of it misses the tumor and is excreted directly via the kidney. Affibody molecules (first de­scribed in 1997) are versatile molecules significantly smaller than MAbs that offer increased stability compared to peptides. They are also highly customizable, allowing increased specificity in a range of applications.

Swedish biotech Affibody AB is a pioneer in the field with decades of innovation in Affibody molecule discovery and engi­neering. It is developing next- generation Radioligand Therapies (RLTs) designed to deliver highly selective tumor targeting across a wide range of cancers and is advancing a novel pipeline fo­cused on oncology indications with high unmet medical need.

Affibody’s lead RLT candidate, ABY-271, is currently being evaluated in a first-in-human clinical study in HER2 positive metastatic breast cancer. This targets a novel epitope (a specific small region on an antigen) compared to concurrent therapies. Additional key areas of interest for Affibody’s RLT pipeline are ad­vanced gastroesophageal adenocarcinoma (GEAC), non-small cell lung cancer, triple negative breast cancer, and pancreatic ductal adenocarcinoma.

THE DEVELOPMENT OF RADIOPHARMA & THERANOSTICS

Theranostics combines therapy and diagnostics, typically combining targeted radioactive agents that first locate cancers with imaging and then delivering treatment directly to the site. It has been described as a “smart missile” that finds specific cells with a diagnostic tracer, then uses a therapeutic isotope to destroy them.

Throughout the past few years, the use of radiotherapy and theranostics in precision oncology has received significant re­newed interest. Modern radiotherapy has changed from a “one-size-fits-all” treatment, into highly personalized therapy targeting specific biological mechanisms, pathways, or molecules. It can also integrate advanced imaging, AI, and systemic therapies. This allows radiation to be delivered with extreme accuracy, reducing damage to healthy tissue while increasing the effective dose to the tumor.

THE USE OF RLTS FOR THE TREATMENT OF METASTATIC BREAST CANCER

Breast cancers are responsible for the deaths of over 40,000 women each year, and this figure has not changed signifi­cantly in 20 years. HER2 is a growth re­ceptor involved in many breast cancers. There is an obvious need for continued ex­ploration to discover effective treatments, highlighting a clear pathway for the appli­cation of other tumor therapies.

Radioligand therapy (RLT) is a tar­geted, systemic cancer treatment combin­ing a radioisotope with a molecule (ligand) that binds to specific cancer cells to destroy them with radiation from within. It is regu­larly used in conjunction with radioligand imaging to form a theranostic approach – where metastatic cancers can be devel­oped and treated with the same targeting molecule, often with PET or SPECT scan­ners.

While some radioligand therapies have already received regulatory approval for the treatment of neuroendocrine and prostatic tumors, none have yet been ap­proved for HER2 cancers. Here, other compounds, such as antibody drug conju­gates (ADCs), are currently used; for ex­ample, Kadcyla (trastuzumab emtasine) and Enhertu (trastuzumab deruxtecan) with dozens more in development.¹

The RLTs available for use in other tu­mors have shown blockbuster successes, emphasizing the opportunity for develop­ment across the board. These include No­vartis’ peptide bound Lutathera (lutetium Lu 177 dotatate) and Pluvicto (lutetium Lu 177 vipivotide tetraxetan), which are ex­pected to have achieved a growth rate of over 10 times by 2031 to more than $6 billion. This is driven by strong clinical ev­idence, as Lutathera has demonstrated a reduced risk of disease progression or death in 72% in certain patients as a first line therapy.²

THE DISCOVERY OF AFFIBODY MOLECULES

Affibody molecules were first de­scribed in 1997 in Nature Biotechnology as small (6.5 kilodaltons) robust three-he­lical protein scaffolds. By substituting dif­ferent amino acids on two of the three he­lixes, researchers at Sweden’s KTH Royal Institute of Technology created a large li­brary consisting of more than 10 billion Affibody® molecules, all with unique bind­ing sites, from which binders to given tar­gets are selected. Using Affibody’s patented platform technology, the mole­cules can be engineered for specific prop­erties, such as resilience, or for specific uses, including conjugation to toxic mole­cules and fusion to protein modules.

These molecules immediately made themselves known as incredibly robust, lending their use to all areas of biotech; for instance, in a hot start PCR kit, where they can withstand multiple heat cycles.³ Compared to antibodies, they are also more practical and less costly to produce as there is no need for antigen immuniza­tion and lengthy mammalian cell line en­gineering and production.⁴

The proprietary Affibody platform has now been clinically validated with more than 1,300 subjects and has demon­strated safety and efficacy for more than 3 years of continuous dosing.

ADVANTAGES OF AFFIBODY MOLECULES OVER ANTIBODIES & PEPTIDES

Affibody molecules are known as a class of antibody mimetics – sitting be­tween antibodies and peptides, Affibody molecules are engineered to co-opt the advantages of both. Having a structured target binding surface area at the same size as a typical antibody, the ability for very high affinity and selectivity binding is much greater than that of most peptides that have a more limited target space. The small size of Affibody molecules (1/20th that of antibodies) allows similar tissue penetration to peptides and enables rapid clearance through the bloodstream, which minimizes non-target organ uptake and rapidly produce high tumor to non-target tissue contrast, which is a major limitation of antibodies. Increased speed due to the small size allows faster imaging; following administration, images can be obtained in mere hours as opposed to days, quickly identifying patients who are likely to re­spond to treatment.

The structure of Affibody molecules allows for significant modification, and Af­fibody has created a library of tens of bil­lions of molecules with unique binding sites enabling a broad target space. The flexibility they have created means alter­ations can be made for specific applica­tions and radioisotopes. The molecules are also more predictable than peptides with behaviors remaining consistent between different molecules allowing for systematic optimization. Rather than trying to make an existing structure work, Affibody can create their own molecule specifically.

The leading Affibody radioligand has been engineered to target a different epi­tope compared to traditional HER2 treat­ments. This enables a multimodal approach that can detect and treat pa­tients with low target-expression in collab­oration with diagnostic companion tools, or those that have become resistant to more conventional therapies and makes it possible for combination with approved HER2 products.

COMPANY MANUFACTURE & FACILITIES

Affibody has more than 2 decades of experience in the sector. There have been more than 1,000 publications of which more than 400 have been specific to ra­diopharmaceuticals.

Affibody’s pipeline also includes im­munology partnership programs in addi­tion to its RLT work. Its leading drug candidate in this field is izokibep, which is currently in Phase 3. With wide applica­tions for indications, such as psoriatic arthritis and hidradenitis suppurativa, izok­ibep addresses autoimmune diseases driven by the protein IL-17 and is best-in-class with superior selectivity and blocking affinity 10 to 100 times stronger than cur­rent leading equivalents.

Affibody has a wealth of expertise, with more than 60 full-time employees forming a team of multidisciplinary experts to create a strong driving force. It also has a long-standing collaboration with Upp­sala University, which provides unique ac­cess to world-class RLT laboratories, animal facilities, and radiochemistry ex­pertise.

CURRENT DIRECTION

Taking an active approach to chal­lenges of regulatory duality as both ra­dioactive substances and drugs, Affibody has been in discussion with regulators across Europe and the US and engaged in extensive pre-clinical work.

Other traditionally significant practi­cal hurdles, such as manufacturing and transport, are diminished by the stability of their molecules, and existing networks are being utilized to create efficient pathways. The reversible albumin binding has multi­ple uses and is well validated in other areas within the field; using an endoge­nous protein carrier, which is widely dis­tributed within the body allows an extended half-life and greater tumor expo­sure, while promoting reduced renal clear­ance, an approach comparatively underutilized within radiopharmaceuticals.

Potential risks to human health have been major factors in the commercial poor-performance of early RLTs.⁵ Con­cerns over radiation-induced myelodyspla­sia (MDS) and acute myeloid leukemia (AML) have been cited, despite these not being found to be significantly different to standard chemotherapeutic agents at the time. The recent successes of peptide bound RLTs exemplify the appreciation of alternatives that can offer improved tissue distribution and therefore reduced cumu­lative doses of radiation.

Despite early concerns over radiation, there are unique benefits that cannot be ignored. As treatment progresses, its po­tential to destroy tumor sites remains strong and resistance against treatment is unlikely to develop due to direct DNA damage. This coupled with the unique epi­tope paves the way for an independent position within the clinical pathway without displacing concomitant treatments.

SIGNIFICANT CLINICAL EVIDENCE

These critical advantages are not just in the scientific model, but have also been demonstrated in preclinical trials, with biodistribution studies using mice bearing HER2-expressing SKOV-3 xenografts.

Affibody’s leading asset, ABY-271, showed accumulation in tumors exceeding that in all other organs and with balanced clearance to provide an increased safety profile. Histopathological evaluation ce­mented this supporting progression to first-in-human trials.

Therapeutic effects were likewise promising. Median survival was extended compared to both controls or trastuzumab (a standard HER2-targeted therapy) with just a single dose of 21 MBq ABY-271, and combination with trastuzumab increased the rate of complete tumor remissions even further.

Furthermore, preclinical results allow us to predict that doses received at the tumor sites being both within the approved therapeutic range and clinically meaning­ful is achievable based off human dosime­try estimates and comparable to existing products.

In October 2025, Affibody an­nounced it had dosed the first human pa­tient in the first part of their open-label, two-part randomized Phase 1 clinical study with ABY-271 in HER2-positive metastatic breast cancer. In December 2025, promising initial results from the first cohort of patients was announced, demonstrating tumor targeting and a fa­vorable safety profile with low uptake in kidneys and other critical organs.

KEY DEVELOPMENTS & A FUTURISTIC OUTLOOK

With successes in its early Phase 1 trial, Affibody decided in December 2025 to advance the Phase 1 clinical study to its second part, in which higher radioactivity levels will be evaluated. Advances and testing will allow the identification of ideal configurations and further safety evalua­tion to inform dose selections for future tri­als.

Developments, such as these aren’t only relevant in the world of HER2 cancers or breast cancers but demonstrate and strengthen the promise of the Affibody molecule as a powerful technology for de­veloping next-generation targeted radio­therapeutics.

The relative successes of recent RLTs compared to historical radioantibodies highlight the increased understanding and uptake of these therapies across the med­ical fields. As antibody therapies continue to excel in medical trials and prove their use, the sector is growing to support their development.

With its place within the treatment pathway where HER2-positive metastatic breast cancers may have become resistant to or are responding to other treatment options, ABY-271 is an encouraging av­enue and may change outcomes signifi­cantly, offering new hope to patients.

REFERENCES

1. Mühlegger M, FDA approved antibody drug conjugates (adcs), Single Use Support. (May 2024) Available at: https://www.susupport.com/blogs/biopharmaceutical-products/fda-ap­proved-antibody-drug-conjugates-adcs (Accessed: January 2026).
2. Novartis Lutathera® significantly reduced risk of disease progression or death by 72% as first-line treatment for patients with advanced gas­troenteropancreatic neuroendocrine tumors (2024) Novartis. Available at: https://www.novartis.com/news/media-releases/novartis-lutathera-significantly-reduced-risk-disease-progression-or-death-72-first-line-treatment-patients-advanced-gastroenteropancreatic-neuroendocrine-tumors.
3. Frejd, F.Y. and Kim, K.-T. (2017) Affibody molecules as engineered pro­tein drugs, Nature News. Available at: https://www.nature.com/arti­cles/emm201735.
4. Zhang, L. & Zhang, H., 2024. Recent advances of affibody molecules in biomedical applications. Bioorganic & Medicinal Chemistry, 113, p.117923. doi:10.1016/j.bmc.2024.117923.
5. Green DJ, Press OW. Whither Radioimmunotherapy: To Be or Not To Be? Cancer Res. 2017 May 1;77(9):2191-2196. doi: 10.1158/0008-5472.CAN-16-2523. Epub 2017 Apr 20. PMID: 28428282; PMCID: PMC5413412.

Fredrik Frejd is Chief Scientific Officer at Affibody. He has more than 20 years of experience in biomedical research with expertise in tumor biology, biotechnological phage display, and therapeutic protein technique with antibody fragments, as well as artificial scaffold proteins. He is an adjunct Professor at the Department of Cancer Precision Medicine at Uppsala University. He is a Board Director of Mergus development AB, Akiram Therapeutics AB, Immuneed AB, and Deputy Board Director of Amylonix AB. He is also a member of Technische Universität Dresden Center for Molecular Bioengineering’s scientific council.