An Expert Report on the Investigational Radiopharmaceutical 161Tb-DOTA-LM3

1. Introduction to 161Tb-DOTA-LM3

Overview as an Investigational Radiopharmaceutical

161Tb-DOTA-LM3 is a novel radiopharmaceutical agent currently under investigation for targeted radionuclide therapy (TRT). This compound integrates the therapeutic radionuclide Terbium-161 ($^{161}$Tb) with a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelator and a tumor-targeting peptide, LM3.[1] The primary therapeutic focus for 161Tb-DOTA-LM3 is on tumors that express the somatostatin receptor (SSTR), with a particular emphasis on neuroendocrine neoplasms (NENs).[1]

Rationale for Development

The development of 161Tb-DOTA-LM3 is driven by the persistent need for more efficacious treatments for NENs, especially in cases of metastatic disease where current options may be limited.[1] This investigational agent aims to harness the unique decay characteristics of $^{161}Tbandthespecifictumor−targetingpropertiesofanSSTRantagonist(LM3)topotentiallyofferanimprovementoverexistingpeptidereceptorradionuclidetherapy(PRRT)agents,suchasthoseutilizingLutetium−177(^{177}$Lu) with SSTR agonists like DOTATATE.[3] The impetus for its advancement is substantially supported by promising preclinical data, which indicate superior therapeutic efficacy and a manageable safety profile when compared to existing standards.[5]

The strategic selection of $^{161}$Tb, with its distinctive emission of β- particles along with a significant cascade of Auger and conversion electrons, differentiates it from radionuclides like $^{177}$Lu, which is primarily a β- emitter.4 Auger electrons possess a very short tissue penetration range but a high linear energy transfer (LET), rendering them highly cytotoxic when the radionuclide decays in immediate proximity to critical cellular structures, such as the cell nucleus or membrane.3 Concurrently, SSTR antagonists, such as LM3, have demonstrated the ability to bind to a greater number of receptor sites on tumor cells and tend to localize predominantly on the cell membrane, in contrast to SSTR agonists which are typically internalized.3 This membrane localization of the antagonist is hypothesized to create a synergistic effect with the short-range Auger electrons emitted by $^{161}$Tb, concentrating their cytotoxic damage at the tumor cell surface. This approach aims to enhance the therapeutic index, particularly for eradicating micrometastases or isolated tumor cells, which are often challenging for therapies relying solely on longer-range β- emissions. Preclinical evidence indeed supports this concept, showingTb-DOTA-LM3 to be more effective than its $^{177}$Lu-labeled counterpart and also more potent than $^{161}$Tb paired with SSTR agonists.5 Thus, 161Tb-DOTA-LM3 represents a thoughtfully designed evolution in PRRT, aiming to overcome limitations of current treatments by optimizing both the radionuclide's destructive potential and the targeting moiety's delivery precision.

## 2. Composition and Properties of 161Tb-DOTA-LM3

### The Radionuclide: Terbium-161 ($^{161}$Tb)

#### Nuclear Properties

Terbium-161 ($^{161}Tb)isasyntheticradioisotopewithaphysicalhalf−liferangingfromapproximately6.934to6.95days.[4,8,14,19]Itundergoesβ−decay,transformingintothestableisotopeDysprosium−161(^{161}$Dy).14 The decay of $^{161}$Tb is characterized by a complex emission spectrum that is particularly advantageous for therapeutic applications. It emits medium-energy β- particles with an average energy (Eβaverage) of approximately 154 keV.4 More significantly for its therapeutic rationale, $^{161}$Tb decay results in a substantial emission of low-energy conversion and Auger electrons. It is estimated that approximately 2.27 such electrons with energies above 3 keV are emitted per decay, contributing to a mean electron energy of about 197 keV per decay.3 Additionally, $^{161}$Tb emits gamma (γ) rays and X-rays, with prominent photon energies around 49 keV (with an intensity of approximately 17-20%) and 75 keV (intensity of approximately 10%), which are suitable for single-photon emission computed tomography (SPECT) imaging, allowing for dosimetry and treatment monitoring.4

Production

The production of $^{161}TbisanindirectprocessinvolvingtheneutronirradiationofhighlyenrichedGadolinium−160(^{160}$Gd) oxide targets within research nuclear reactors.14 The nuclear reaction sequence is 160Gd(n,γ)→161Gd. The resulting $^{161}$Gd is a short-lived intermediate (half-life of 3.66 minutes) that rapidly decays via β- emission to $^{161}$Tb.14 Subsequent radiochemical separation processes, typically involving cation exchange and extraction chromatography, are employed to isolate no-carrier-added (n.c.a.) $^{161}$Tb, ensuring high specific activity.14

#### Comparison with Lutetium-177 ($^{177}$Lu)

Lutetium-177 is a well-established therapeutic radionuclide in PRRT. Comparing $^{161}$Tb with $^{177}$Lu reveals several key distinctions and similarities:

Half-life: The half-life of $^{161}$Tb (6.934-6.95 days) is marginally longer than that of $^{177}$Lu (approximately 6.65-6.73 days).[14]
Beta Emissions: Both are β- emitters, making them suitable for delivering therapeutic radiation doses to tumor tissues.[5]
Auger/Conversion Electrons: The principal advantage of $^{161}$Tb lies in its copious emission of Auger and conversion electrons. These low-energy electrons have a very short range in tissue (micrometers) but deposit their energy densely (high LET). This results in significantly higher localized radiation doses at cellular and subcellular levels compared to $^{177}$Lu, which emits fewer such electrons. The dose deposition from $^{161}$Tb at ranges less than 0.1 mm can be more than double that of $^{177}Lu,offeringapotentialtherapeuticadvantage,particularlyagainstsinglecancercellsormicrometastases.[3,4,5,8,10,12,14,15,21]∗∗∗ImagingCapabilities:∗∗Bothradionuclidesemitγ−rayssuitableforSPECTimaging,facilitatingpatient−specificdosimetryandtherapeuticmonitoring.Thedistinctphotonenergiesallowforthepossibilityofsimultaneousimagingifbothradionuclideswereco−administered,thoughthisisnotthestandardapplicationfor161Tb−DOTA−LM3.[14]Thefollowingtablesummarizesthekeynuclearproperties:∗∗Table1:ComparativeNuclearPropertiesofTerbium−161andLutetium−177∗∗∣Property∣Terbium−161(^{161}Tb)∣Lutetium−177(^{177}$Lu) | | :--- | :--- | :--- | | Half-life (T1/2) | 6.934 - 6.95 days [4] | ~6.65 - 6.73 days [1] | | Decay Mode | β- [14] | β- | | Daughter Nuclide | $^{161}$Dy (stable) [14] | $^{177}$Hf (stable) | | β- Eavg | ~154 keV [4] | ~133 keV [24] | | β- Emax | 593 keV [19] | 497 keV | | Major γ-ray Energies (keV) (Intensity) | 49 keV (~17-20%), 75 keV (~10%) [4] | 113 keV (~6.4%), 208 keV (~11%) [24] | | Auger/Conversion Electron Yield per Decay | High (~2.27 electrons >3 keV) [4] | Lower | | Mean Auger/Conversion Electron Energy (keV per decay) | ~197 keV (total electron energy ~202.5 keV) [14] | Lower (total electron energy ~147.9 keV) [24] |

The Chelator: DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)

DOTA, also referred to as tetraxetan, is a macrocyclic compound widely employed as a chelator in radiopharmaceuticals.[1] Its chemical structure features a 12-membered tetraaza (four nitrogen atoms) ring with four carboxymethyl arms (CH2COOH) attached to these nitrogen atoms. The primary role of DOTA in 161Tb-DOTA-LM3 is to securely bind the $^{161}$Tb radionuclide and link it to the LM3 targeting peptide.[1] DOTA exhibits high affinity for trivalent lanthanide ions such as Tb3+ and Lu3+, typically functioning as an octadentate ligand by coordinating the metal ion through its four nitrogen atoms and four deprotonated carboxylate groups.[20] This strong and stable chelation is critical for radiopharmaceutical applications, as it prevents the premature release of the toxic radionuclide in vivo before it reaches the tumor target, thereby minimizing systemic toxicity and ensuring efficient delivery of the radioactive payload to the cancer cells.[1] DOTA's chemical versatility allows for its conjugation to various biomolecules, including peptides and antibodies, making it a cornerstone in the design of targeted radiotherapeutic and diagnostic agents.[20]

The Targeting Moiety: LM3

LM3 is a synthetic peptide analogue that functions as a potent and selective antagonist of the somatostatin receptor subtype 2 (SSTR2).[1] The amino acid sequence of LM3, as disclosed in patent literature, isD-Tyr-NH2].[1] SSTR2 is a G protein-coupled receptor that is frequently overexpressed on the cell surface of various neuroendocrine tumors, making it an attractive target for diagnostic imaging and radionuclide therapy.[1]

The choice of an SSTR antagonist like LM3, as opposed to an SSTR agonist (e.g., DOTATATE or DOTATOC), is based on several pharmacological advantages observed in preclinical and clinical settings. SSTR antagonists have been shown to bind to a significantly higher number of receptor sites on tumor cells compared to agonists.[3] Furthermore, antagonists tend to remain bound to the cell surface membrane for extended periods, whereas agonists are typically internalized into the cell following receptor binding.[3] This prolonged membrane localization is particularly relevant for therapy with $^{161}$Tb, as the short-range, high-LET Auger and conversion electrons emitted by $^{161}$Tb can deposit their cytotoxic energy most effectively when the radionuclide is in close proximity to or on the cell membrane.

The strategic combination of $^{161}$Tb's potent, localized radiation effects with DOTA's stable chelation and LM3's enhanced tumor targeting via SSTR2 antagonism forms the fundamental basis of 161Tb-DOTA-LM3's therapeutic design. The aim is to deliver a highly concentrated radiolytic insult directly to the tumor cell membrane and its immediate vicinity. This approach leverages the increased receptor availability for antagonists and the unique decay properties of $^{161}$Tb, particularly its Auger electron emissions, which are theorized to be exceptionally effective when the radionuclide is positioned at the cell surface, as facilitated by the LM3 antagonist. Preclinical evidence has substantiated this rationale, demonstrating thatTb-DOTA-LM3 exhibits superior cytotoxicity and anti-tumor efficacy compared to both its $^{177}$Lu-labeled counterpart and $^{161}$Tb complexed with SSTR agonists.[5] This suggests that the LM3 antagonist component is critical in maximizing the therapeutic potential of $^{161}$Tb.

3. Mechanism of Action

Targeting SSTR2-Expressing Cells

The primary mechanism of action of 161Tb-DOTA-LM3 begins with the highly specific binding of its LM3 component to the somatostatin receptor subtype 2 (SSTR2).[1] SSTR2 is known to be overexpressed on the cell membranes of many neuroendocrine tumors (NETs) and their metastases, while its expression in most normal tissues is comparatively low.[3] This differential expression provides a basis for the selective delivery of the attached radionuclide, $^{161}$Tb, to the tumor cells.

Cellular Localization and Implications for Auger Electron Therapy

A critical aspect of the mechanism of 161Tb-DOTA-LM3 is the cellular localization dictated by the LM3 antagonist. Unlike SSTR agonists (such as DOTATATE or DOTATOC), which are internalized by the cell upon receptor binding through endocytosis, SSTR antagonists like LM3 predominantly remain bound to the cell surface.[3] This membrane localization is of paramount importance for maximizing the therapeutic efficacy of $^{161}$Tb. The rationale is that the short-range, high-LET Auger and conversion electrons emitted by $^{161}$Tb have a very limited path length in tissue (typically in the nanometer to micrometer range). For these electrons to exert their potent cytotoxic effects, the radionuclide must be in extremely close proximity to critical cellular targets. By anchoring $^{161}$Tb to the cell membrane via LM3, these highly damaging electrons are released directly at or very near the cell surface, a vital cellular structure. This targeted energy deposition can lead to significant membrane damage, disruption of membrane-bound signaling proteins, and potentially trigger apoptotic pathways distinct from or complementary to those induced by DNA damage from more deeply penetrating radiation.[3]

Radiolytic Effects of Terbium-161 Emissions

Once 161Tb-DOTA-LM3 is localized at the tumor cell surface, the decay of $^{161}$Tb initiates the radiolytic damage. $^{161}$Tb emits medium-energy β- particles, which can travel several millimeters in tissue.[4] These β- particles contribute to the overall tumoricidal effect by irradiating cells within the tumor mass, including those that may not directly bind the radiopharmaceutical (crossfire effect).

However, the unique therapeutic advantage of $^{161}$Tb is largely attributed to its co-emission of a dense shower of low-energy Auger and conversion electrons.[3] These electrons deposit their energy very densely over extremely short distances. If the radionuclide is situated on the cell membrane, this high-LET radiation can cause severe, localized damage to membrane lipids, proteins, and nearby structures, potentially leading to rapid cell death. If any portion of the antagonist-radionuclide complex were to be advected close to the nucleus, these electrons could also induce complex DNA double-strand breaks, which are difficult for cancer cells to repair. The combination of the longer-range β- particle emissions, capable of reaching cells further from the bound radiopharmaceutical, and the highly potent, very short-range Auger/conversion electrons, provides a dual mechanism of action. This "one-two punch" is theorized to be effective against both larger tumor burdens (via β- emissions) and single disseminated cancer cells or small micrometastases (primarily via Auger/conversion electrons), which are often resistant to conventional therapies.[3]

The therapeutic strategy of 161Tb-DOTA-LM3 is thus predicated on the synergistic interplay between the enhanced tumor targeting and membrane localization afforded by the SSTR antagonist LM3, and the potent, short-range cytotoxic effects of the Auger/conversion electrons emitted by $^{161}$Tb. This differs fundamentally from therapies relying solely on longer-range beta emitters or those using internalizing agonists, where the radionuclide is translocated into the cytoplasm or nucleus. While internalization can be beneficial for DNA-damaging radionuclides, the membrane-focused attack by $^{161}Tb′sAugerelectronswhendeliveredbyanantagonistoffersadistinctmechanism.Preclinicalstudieshavesupportedthisconcept,demonstratingthatTb−DOTA−LM3issignificantlymorepotentinvitroandinvivothan[^{177}$Lu]Lu-DOTA-LM3 (which lacks the rich Auger electron spectrum) and also more effective than $^{161}$Tb when combined with internalizing SSTR agonists.[5] This suggests that the specific combination of $^{161}$Tb with a membrane-localizing antagonist is key to unlocking its full therapeutic potential.

4. Preclinical Development

The preclinical development of 161Tb-DOTA-LM3 has encompassed a range of in vitro and in vivo studies designed to evaluate its binding characteristics, cellular effects, therapeutic efficacy, and safety profile.

In Vitro Studies

Cell Uptake and Internalization

Studies utilizing SSTR-positive tumor cell lines, such as the rat pancreatic cancer cell line AR42J, have demonstrated significantly higher cellular uptake ofTb-DOTA-LM3 compared to SSTR agonists likeTb-DOTATOC. For instance,Tb-DOTA-LM3 showed approximately 70% total added activity associated with AR42J cells after a 2-hour incubation, which was four to six times higher than the uptake observed for the agonistTb-DOTATOC (around 10%).[5]

Consistent with its antagonist nature, the internalization ofTb-DOTA-LM3 was limited. Only about 9% of the cell-associated activity was found to be internalized, whereas SSTR agonists like DOTATOC and DOTATOC-NLS (a nuclear-localizing sequence variant) showed much higher internalization rates of approximately 81% and 84%, respectively.[5] Furthermore, nuclear localization of DOTA-LM3 was minimal, with less than 2% of the total uptake found in the cellular nucleus, similar to DOTATOC but less than DOTATOC-NLS.[5] This predominant membrane localization is a key feature supporting its proposed mechanism of action with $^{161}$Tb.

Binding Affinity to SSTR2

While specific equilibrium dissociation constant (Kd) or half-maximal inhibitory concentration (IC50) values for the binding of 161Tb-DOTA-LM3 to SSTR2 are not explicitly detailed in the provided summaries, LM3 is consistently characterized as an SSTR2 antagonist.[1] The high levels of specific cell uptake observed in vitro strongly suggest a high binding affinity of the DOTA-LM3 conjugate for SSTR2 expressed on tumor cells.[5]

Cytotoxicity and Cell Survival Assays

In vitro cytotoxicity assays have consistently shown the superior potency ofTb-DOTA-LM3. In SSTR-positive AR42J tumor cells,Tb-DOTA-LM3 was significantly more effective at reducing cell viability and survival compared to [$^{177}$Lu]Lu-DOTA-LM3 and also compared to $^{161}$Tb or $^{177}$Lu when labeled to SSTR agonists.[5] The half-maximal effective concentration (EC50) forTb-DOTA-LM3 in reducing AR42J cell viability was determined to be 0.010 MBq/mL. This potency was 102-fold greater than that of [$^{177}Lu]Lu−DOTA−LM3andanstriking820−foldgreaterthanthatoftheclinicallyestablished[^{177}$Lu]Lu-DOTATOC (EC50 of 8.2 MBq/mL).[5] Colony-forming assays further corroborated these findings, demonstrating thatTb-DOTA-LM3 more effectively reduced tumor cell survival than its $^{177}$Lu-labeled counterpart.[5]

In Vivo Animal Studies

Preclinical in vivo studies, primarily conducted in mice bearing SSTR-positive tumor xenografts (e.g., AR42J), have further elucidated the biodistribution, dosimetry, efficacy, and safety of 161Tb-DOTA-LM3.

Biodistribution and Pharmacokinetics (ADME)

Consistent with the properties of SSTR antagonists, DOTA-LM3-based radiopharmaceuticals have shown higher tumor accumulation compared to agonist-based agents in animal models.[3] Specific biodistribution studies withTb-DOTA-LM3 in mice confirmed favorable tumor uptake and retention characteristics.[11] Detailed pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion profiles are still emerging from ongoing research.

Dosimetry

Dosimetry calculations based on biodistribution data in immunocompetent mice indicated that the absorbed radiation dose to organs was generally higher for the SSTR antagonist DOTA-LM3 compared to the SSTR agonist DOTATATE. Furthermore, the use of $^{161}$Tb resulted in higher absorbed doses compared to $^{177}$Lu, reflecting its different emission profile.8

#### Therapeutic Efficacy

Therapy studies in tumor-bearing mice have provided compelling evidence of the superior anti-tumor efficacy ofTb-DOTA-LM3. It was significantly more effective in delaying tumor growth and prolonging the survival of mice compared to [$^{177}$Lu]Lu-DOTA-LM3.5 While $^{161}$Tb also showed a therapeutic advantage over $^{177}$Lu when combined with the agonist DOTATOC, the combination of $^{161}$Tb with the antagonist LM3 (Tb-DOTA-LM3) was demonstrably superior to all other tested combinations, including $^{161}$Tb-DOTATOC.5 For instance, in AR42J tumor-bearing mice,Tb-DOTA-LM3 treatment led to the most significant tumor growth inhibition and the longest survival outcomes.5

Safety and Tolerability

Tolerability studies in immunocompetent mice have assessed the safety profile ofTb-DOTA-LM3 andTb-DOTATATE.[15] At therapeutic activity levels of 20 MBq per mouse,Tb-DOTA-LM3 was reported to be well tolerated, with no major hematological changes observed.[15] However, at higher injected activities (100 MBq per mouse), transient hematological effects were noted. These included a 40-50% reduction in lymphocyte counts by Day 10 (irrespective of the radionuclide), and more pronounced decreases in thrombocyte (30-50% lower) and erythrocyte (6-12% lower) counts with the SSTR antagonistTb-DOTA-LM3 compared to the agonistTb-DOTATATE. Importantly, these blood cell counts recovered to normal ranges by Day 56 of the study.[15] Histological examination of organs such as the kidneys, liver, and spleen revealed only minimal abnormalities in treated mice, and these did not show a clear correlation with the absorbed organ dose.[15] The overall conclusion from these tolerability studies is that despite the increased absorbed radiation dose delivered by $^{161}$Tb compared to $^{177}$Lu,Tb-DOTA-LM3 is expected to be safe at activity levels comparable to those recommended for its $^{177}$Lu-based analogues.[15]

The collective preclinical data strongly suggests that 161Tb-DOTA-LM3 possesses a superior anti-tumor efficacy profile compared to both $^{177}$Lu-based radiopharmaceuticals and $^{161}$Tb when combined with SSTR agonists. This enhanced efficacy is attributed to the synergistic combination of $^{161}$Tb's potent Auger electron emissions and the favorable pharmacokinetics (higher tumor accumulation and membrane localization) conferred by the LM3 antagonist. The observed in vitro cytotoxicity, translating to significant tumor growth delay and improved survival in animal models, underscores this advantage. The finding thatTb-DOTA-LM3 outperforms evenTb-DOTATOC highlights the critical role of the LM3 antagonist in maximizing the therapeutic utility of $^{161}Tb.WhilehigherdosesofTb−DOTA−LM3caninducemorepronouncedtransienthematologicaleffectsthanagonist−basedtherapies,theseeffectsappeartobemanageableandrecoverable,supportingitsprogressionintoclinicalevaluation.∗∗Table2:SummaryofKeyPreclinicalEfficacyStudiesfor161Tb−DOTA−LM3∗∗∣StudyType∣Model(CellLine/AnimalModel)∣Compound(s)Tested∣Comparator(s)∣KeyEfficacyOutcome∣KeyReference(s)∣∣:−−−∣:−−−∣:−−−∣:−−−∣:−−−∣:−−−∣∣InVitro∣AR42Jcells∣Tb−DOTA−LM3∣[^{177}Lu]Lu−DOTA−LM3,[^{177}$Lu]Lu-DOTATOC | EC50 for cell viability:Tb-DOTA-LM3 = 0.010 MBq/mL (102x more potent than [$^{177}Lu]Lu−DOTA−LM3;820xmorepotentthan[^{177}$Lu]Lu-DOTATOC). Superior reduction in cell survival. | 5 |

| In Vitro | AR42J cells |Tb-DOTA-LM3 |Tb-DOTATOC,Tb-DOTATOC-NLS |Tb-DOTA-LM3 more potent than $^{161}Tb−agonists.∣[5]∣∣InVivo(Therapy)∣AR42Jtumor−bearingmice∣Tb−DOTA−LM3∣[^{177}Lu]Lu−DOTA−LM3,Tb−DOTATOC,[^{177}Lu]Lu−DOTATOC∣Significantlymoreeffectiveindelayingtumorgrowthandprolongingsurvival.Mediansurvival>49daysvs.48.5daysfor[^{177}Lu]Lu−DOTA−LM3and 20daysforDOTATOCgroups.Tumorgrowthdelay44daysvs.35daysfor[^{177}$Lu]Lu-DOTA-LM3. | 5 |

| In Vivo (Therapy) | AR42J tumor-bearing mice |Tb-DOTA-LM3 |Tb-DOTATATE, Untreated control | Median survival (1x5 MBq): 19 days vs. 16.5 days vs. 8 days. Median survival (2x5 MBq): 29 days vs. 30 days. (Note: Uses $^{149}$Tb but compares antagonist to agonist) | 18 |

## 5. Clinical Development: Focus on NCT05359146 ("Beta Plus Study")

The clinical development of 161Tb-DOTA-LM3 is currently spearheaded by the "Beta Plus Study," registered under the identifier NCT05359146.6

### Study Design and Sponsorship

The Beta Plus Study is an investigator-initiated trial (IIT), characterized as a single-center, open-label study, primarily conducted at the University Hospital Basel, Switzerland.9 It is classified as an Early Phase 1 or Phase 0/I trial, reflecting its exploratory nature in first-in-human administration.6 The study is a collaborative effort involving the University Hospital Basel, the Paul Scherrer Institute (PSI) for radionuclide development and radiopharmaceutical manufacturing, and is supported by the Swiss National Science Foundation.6

The study is structured in distinct phases:

* **Phase 0A (Dosimetry):** This completed phase aimed to evaluate the dosimetry ofTb-DOTA-LM3. Patients received an infusion of 1 GBq ofTb-DOTA-LM3 (with a maximum peptide mass of 100 µg). [$^{177}$Lu]Lu-DOTATOC served as a comparator for dosimetry assessments. This phase enrolled 8 patients.6

* **Phase 0B (Dose Escalation/Peptide Mass Scaling):** This planned phase intends to escalate the administered activity ofTb-DOTA-LM3 and explore different peptide masses. Planned dose levels include 2-3 GBq with a maximum peptide mass of 100 µg, and 2-3 GBq with a peptide mass of 300-400 µg. Higher activities, potentially 4-8 GBq, are also under consideration. This phase is expected to enroll 4-8 patients and involve up to 4 treatment cycles.6

### Patient Population and Intervention

The target patient population for the Beta Plus Study comprises individuals with metastatic, hormone-active gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of Grade 1 or Grade 2 histology.4 The intervention involves the intravenous administration ofTb-DOTA-LM3.4

### Objectives and Endpoints

The primary objectives of this early-phase study are to assess the safety, tolerability, and radiation dosimetry ofTb-DOTA-LM3 in human subjects.6 Secondary objectives likely include preliminary evaluations of anti-tumor activity, such as changes in tumor markers and responses observed on imaging, as well as determining the therapeutic index relative to established treatments like [$^{177}$Lu]Lu-DOTATOC.4

Timeline

The Phase 0A (Dosimetry) part of the study enrolled its first patient on April 17, 2023, and the last patient for this phase was enrolled on February 27, 2024.[6] The Phase 0B (Dose Escalation) component was anticipated to commence in the third quarter of 2024.[6] The overall study was projected to begin in December 2022.[13]

Preliminary Findings (First-in-Human Data from Phase 0A)

Initial results from the first-in-human administration ofTb-DOTA-LM3, primarily from the Phase 0A dosimetry cohort, have been reported:

Dosimetry and Tumor Uptake: Data from a 78-year-old male patient with a metastatic ileal NET who received a 1 GBq test infusion ofTb-DOTA-LM3 demonstrated favorable characteristics.[4] SPECT/CT imaging performed after administration showed good image quality, enabling quantitative assessment despite the low energy of some of $^{161}$Tb's gamma emissions.[4] Significantly, high tumor accumulation was observed, with a mean tumor absorbed dose calculated at 28 Gy/GBq (range 18-39 Gy/GBq) in liver metastases. The Paul Scherrer Institute reported that the irradiation to tumor cells was approximately 9 times higher than that achieved with previous standard treatments (contextually referring to $^{177}$Lu-DOTATOC).[16] The radiopharmaceutical exhibited a long mean tumor biological half-life of 130 hours (range 123-135 hours) in liver metastases.[4] Absorbed doses to critical normal organs were reported as 0.31 Gy/GBq for bone marrow, 3.33 Gy/GBq for kidneys, and 6.86 Gy/GBq for the spleen.[4]
Safety and Tolerability: In the first patient, the 1 GBq infusion ofTb-DOTA-LM3 was generally well tolerated.[4] Observed adverse events included Grade 1 thrombocytopenia and Grade 3 lymphocytopenia (it was noted that Grade 2 lymphocytopenia was pre-existing in this patient).[4]
Early Signs of Efficacy: A notable decrease in the tumor marker chromogranin A was observed, falling from 522 µg/L to 359 µg/L within two months following the single 1 GBq infusion ofTb-DOTA-LM3, suggesting biological activity.[4]

GMP Manufacturing

TheTb-DOTA-LM3 used in the Beta Plus Study is manufactured under Good Manufacturing Practice (GMP) conditions at the Paul Scherrer Institute.[6] This involves an automated purification process for the crude $^{161}$Tb radionuclide and synthesis of the final radiopharmaceutical product using disposable cassettes within controlled clean room environments to ensure sterility and quality suitable for human administration.[6]

The initial human data from the NCT05359146 study provides critical early validation of the therapeutic concept behindTb-DOTA-LM3. The confirmation of high tumor accumulation and substantially greater tumor-absorbed radiation doses compared to standard therapies, achieved with a manageable safety profile at the initial dose level, is highly encouraging. This successful translation from promising preclinical findings—which predicted superior tumor uptake and efficacy—to the human setting is a significant milestone. The observed reduction in a key tumor marker like chromogranin A, even after a single low-dose administration, offers a preliminary yet positive indication of the agent's biological activity. These early clinical successes reinforce the rationale that the unique combination of $^{161}Tb′sdecaypropertieswiththeSSTRantagonistLM3couldindeedleadtoamoreeffectivePRRToptionforpatientswithNETs.∗∗Table3:OverviewofClinicalTrialNCT05359146(Tb−DOTA−LM3"BetaPlusStudy")∗∗∣Feature∣Details∣∣:−−−∣:−−−∣∣∗∗OfficialTitle∗∗∣CombinedBeta−PlusAugerElectronTherapyUsingaNovelSomatostatinReceptorSubtype2AntagonistLabelledWithTerbium−161(^{161}$Tb-DOTA-LM3): Beta Plus Study 6 |

| **NCT Number** | NCT05359146 6 |

| **Phase** | Early Phase 1 / Phase 0A & 0B 6 |

| **Sponsor / Collaborators** | Universitätsspital Basel (Sponsor); Paul Scherrer Institute (PSI), Swiss National Science Foundation (Collaborators) 6 |

| **Status** | Recruiting (as of latest Synapse update for Phase 0B); Phase 0A Completed 6 |

| **Key Objectives** | **Phase 0A:** Dosimetry ofTb-DOTA-LM3, comparison with [$^{177}$Lu]Lu-DOTATOC. Phase 0B: Dose escalation and peptide mass scaling ofTb-DOTA-LM3, safety, tolerability. 6 |

| Patient Population | Metastatic, hormone-active GEP-NETs (Grade 1 or 2) 4 |

| Intervention |Tb-DOTA-LM3 via intravenous infusion. Phase 0A: 1 GBq (max 100 µg peptide). Phase 0B: Planned 2-3 GBq (max 100 µg or 300-400 µg peptide), potentially 4-8 GBq. 4 |

| Primary Outcome Measures | Dosimetry (absorbed doses to tumors and organs), Safety and Tolerability (adverse events) 4 |

| Secondary Outcome Measures | Tumor marker response (e.g., Chromogranin A), Imaging response (SPECT/CT), Therapeutic Index 4 |

| Key Reported Findings (Phase 0A) | - Mean tumor absorbed dose: 28 (18-39) Gy/GBq in liver metastases. <br> - Tumor irradiation ~9x higher than standard. <br> - Organ doses (Gy/GBq): Bone Marrow 0.31, Kidneys 3.33, Spleen 6.86. <br> - Safety: Grade 1 thrombocytopenia, Grade 3 lymphocytopenia (pre-existing G2). <br> - Efficacy signal: Chromogranin A decrease (522 to 359 µg/L) post 1 GBq. 4 |

6. Therapeutic Potential and Comparative Assessment

Potential Advantages over Existing Therapies

161Tb-DOTA-LM3 holds the promise of several therapeutic advantages over currently established PRRT agents, such as $^{177}$Lu-DOTATATE:

Enhanced Therapeutic Efficacy from Auger Electrons: The most significant distinguishing feature of $^{161}$Tb is its co-emission of a substantial number of low-energy Auger and conversion electrons. These electrons have a very short range but high LET, leading to dense ionization and highly localized energy deposition. This characteristic is particularly advantageous for eradicating single cancer cells, small cell clusters, and micrometastases, which may be less effectively targeted by the longer-range β- particles from $^{177}$Lu alone.[3]
Higher Tumor Accumulation with SSTR Antagonist: The LM3 component, being an SSTR antagonist, binds to a greater number of SSTR2 sites on tumor cells compared to SSTR agonists. This can lead to higher overall accumulation and retention of the radiopharmaceutical in the tumor.[3]
Improved Tumor-to-Organ Dose Ratios: The combination of higher tumor uptake due to the antagonist and the potent localized energy deposition from $^{161}$Tb's Auger electrons has the potential to improve the therapeutic index. Early clinical data from the first-in-human administration indicated a tumor irradiation approximately 9 times higher than that of the previous standard treatment, suggesting a favorable dosimetry profile.[4]

Targeted Patient Populations

The primary patient population for 161Tb-DOTA-LM3 is individuals with SSTR2-positive NETs. This includes, but is not limited to, GEP-NETs, which are the focus of the ongoing Beta Plus Study.[1] Given its potential for enhanced efficacy, 161Tb-DOTA-LM3 might also be particularly beneficial for patients who have shown a suboptimal response to, or have become refractory to, existing $^{177}$Lu-based PRRT.[7]

Theranostic Approach

Terbium-161 emits gamma rays (notably at 49 keV and 75 keV) that are suitable for SPECT imaging.[4] This allows for pre-therapeutic imaging to confirm tumor targeting and uptake, as well as post-therapeutic imaging for patient-specific dosimetry and assessment of treatment response. This capability aligns 161Tb-DOTA-LM3 with the theranostic paradigm, where the same or chemically similar radionuclide-ligand combination can be used for both diagnostic imaging and targeted therapy, facilitating personalized treatment strategies.

The potential for 161Tb-DOTA-LM3 to establish a new standard of care in PRRT for NETs is significant. The substantially higher tumor irradiation observed in initial human studies [16], coupled with the theoretical advantages of combining an SSTR antagonist with the potent, short-range Auger electrons of $^{161}$Tb [3], suggests a pathway to improved clinical outcomes. If these early dosimetry advantages translate into superior efficacy (e.g., higher objective response rates, prolonged progression-free survival) while maintaining a manageable safety profile in larger clinical trials, 161Tb-DOTA-LM3 could indeed represent a paradigm shift. Its particular strength may lie in addressing micrometastatic disease, a common challenge in the long-term management of NETs, due to the highly localized and potent cell-killing capability of the Auger electrons.

Table 4: Comparative Dosimetry and Safety Profile of 161Tb-DOTA-LM3 vs. Comparators (from preclinical/early clinical data)

Radiopharmaceutical	Tumor Absorbed Dose (Gy/GBq)	Kidney Absorbed Dose (Gy/GBq)	Bone Marrow Absorbed Dose (Gy/GBq)	Key Safety Findings/Toxicities	Reference(s)
Tb-DOTA-LM3 (Human, Phase 0A)	28 (mean, range 18-39) in liver metastases	3.33	0.31	Grade 1 thrombocytopenia, Grade 3 lymphocytopenia (G2 pre-existing)	4
Tb-DOTA-LM3 (Mice, 100 MBq)	Higher than agonist & $^{177}$Lu	Higher than agonist & $^{177}$Lu \$	N/A directly, but hematologic effects noted \	Transient lymphopenia, thrombocytopenia, erythrocytopenia (recovered by Day 56); Minimal organ abnormalities \	15 \
\	[^{177}$Lu]Lu-DOTA-LM3 (Mice, 100 MBq)	Lower than $^{161}$Tb-DOTA-LM3	Lower than $^{161}$Tb-DOTA-LM3	N/A directly, but hematologic effects noted	Similar pattern but less pronounced hematological effects than $^{161}$Tb-DOTA-LM3 \$
\	Tb-DOTATATE (Mice, 100 MBq) \	Lower than DOTA-LM3 \	Lower than DOTA-LM3 \	N/A directly, but hematologic effects noted \	Less pronounced hematological effects than antagonist \
\	[^{177}$Lu]Lu-DOTATOC (Clinical Standard)	Generally lower than reported for $^{161}$Tb-DOTA-LM3 in first human data	Variable, a key dose-limiting organ	Hematotoxicity is a known concern	Established safety profile including hematotoxicity and nephrotoxicity

Note: Direct head-to-head comparative human dosimetry and safety data at therapeutic doses are still emerging from ongoing trials like NCT05359146. Mouse data provides an indication of relative effects.

7. Development and Regulatory Landscape

Key Institutions Involved in Development

The development of 161Tb-DOTA-LM3 is a collaborative effort, primarily driven by leading academic and research institutions in Switzerland:

Paul Scherrer Institute (PSI), Villigen, Switzerland: PSI has been instrumental in the development of the $^{161}$Tb radionuclide itself and is responsible for the GMP-compliant manufacturing ofTb-DOTA-LM3 for the ongoing clinical trials.[6]
University Hospital Basel, Basel, Switzerland: This institution is leading the clinical investigation of 161Tb-DOTA-LM3, notably the "Beta Plus Study" (NCT05359146).[6]
Other Collaborators: Preclinical research has also involved contributions from ETH Zurich, the Sahlgrenska Academy at the University of Gothenburg, and the Institut Laue-Langevin, indicating a broader European research network.[16]

Patent Status

The intellectual property surrounding 161Tb-DOTA-LM3 appears to be secured through patent applications.

U.S. Patent Application Publication No. US20230293736A1, and its corresponding international application PCT/EP2021/080220, claim radiopeptides comprising $^{161}$Tb, a chelator (specifically including DOTA and its derivatives), and an SSTR antagonist (specifically including LM3) for the treatment of tumor diseases.[1]
The inventors listed on this patent application include Cristina Müller, Roger Schibli, Nicolas Philip Van Der Meulen, Francesca Borgna, Damian Wild, and Melpomeni Fani, who are affiliated with the key developing institutions.[1]
The original assignees are listed as the Paul Scherrer Institut and Universitaet Basel.[1]
Competing interest statements in research publications also confirm that the University Hospital Basel and the Paul Scherrer Institute have filed a patent concerningTb-DOTA-LM3, with R. Schibli, N. van der Meulen, and C. Mueller named as co-inventors, aligning with the patent application details.[8]

Orphan Drug Designation Status

The provided information does not contain specific details regarding Orphan Drug Designation (ODD) for 161Tb-DOTA-LM3 from regulatory bodies such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). While Lutetium Lu 177 dotatate has received ODD for GEP-NETs [33], and other SSTR-targeted agents have various regulatory statuses [23], the ODD status for 161Tb-DOTA-LM3 itself is not mentioned in the available materials. Synapse data indicates its highest development phase as Early Phase 1 with no specific regulatory designations listed.[9]

The development trajectory of 161Tb-DOTA-LM3 is notably characterized by its strong foundation in academic and publicly funded research institutions. This collaborative model, involving institutions like PSI and University Hospital Basel, with support from entities such as the Swiss National Science Foundation [13], underscores a pathway for innovation in radiopharmaceuticals that can originate outside the traditional large pharmaceutical industry pipeline. The securing of intellectual property by these pioneering institutions is a crucial step in protecting their innovations and facilitating further development and potential commercialization.

8. Summary and Future Perspectives

Recapitulation of Key Findings

161Tb-DOTA-LM3 has emerged as a highly promising investigational radiopharmaceutical for the targeted treatment of SSTR2-expressing neuroendocrine tumors. Its design leverages the unique nuclear properties of Terbium-161, particularly its dual emission of therapeutic β- particles and highly potent, short-range Auger/conversion electrons. This is combined with the DOTA chelator for stable radionuclide conjugation and the LM3 peptide, an SSTR2 antagonist, which has demonstrated superior tumor targeting and membrane localization compared to SSTR agonists.

Preclinical in vitro and in vivo studies have consistently shown thatTb-DOTA-LM3 exhibits significantly enhanced cytotoxicity and anti-tumor efficacy compared to its $^{177}$Lu-labeled counterpart and also $^{161}$Tb complexed with SSTR agonists. This superiority is attributed to the synergistic effect of $^{161}$Tb's Auger electrons acting at the cell membrane where the LM3 antagonist localizes. The first-in-human data from the "Beta Plus Study" (NCT05359146) has provided initial clinical validation, demonstrating remarkably high tumor radiation doses—reportedly up to nine times that of standard therapy—along with a manageable safety profile and early signs of biological activity in patients with GEP-NETs.

Potential Impact on NET Treatment Paradigm

Should the promising early findings be substantiated in larger, later-phase clinical trials, 161Tb-DOTA-LM3 has the potential to significantly alter the treatment landscape for NETs. It could offer a more potent PRRT option, potentially leading to improved objective response rates, longer duration of response, and ultimately, enhanced survival for patients. Its unique ability to deliver high LET radiation via Auger electrons makes it particularly interesting for addressing micrometastatic disease or individual cancer cells, which are often a source of relapse and are challenging to eradicate with therapies relying solely on longer-range β- emissions. This could translate into more durable remissions and better outcomes for patients, including those who may be refractory or have had a suboptimal response to current $^{177}$Lu-based PRRT.

Future Research Directions and Challenges

The path forward for 161Tb-DOTA-LM3 involves several critical steps and potential challenges:

Clinical Trials: Successful completion of the ongoing Phase 0B/I dose-escalation and expansion cohorts of the NCT05359146 study is paramount to establish the optimal therapeutic dose and further confirm safety. Subsequently, larger, randomized controlled trials will be necessary to definitively compare the efficacy and safety of 161Tb-DOTA-LM3 against the current standard-of-care PRRT, such as $^{177}$Lu-DOTATATE.
Long-Term Safety: Comprehensive long-term follow-up of treated patients will be essential to monitor for any late-onset toxicities, particularly concerning renal function and hematological parameters, given the novel radionuclide and the higher radiation doses delivered to tumors.
Expanded Indications: Exploration of 161Tb-DOTA-LM3 in other SSTR2-positive malignancies beyond GEP-NETs could broaden its therapeutic utility.
Radionuclide Production and Supply: A significant challenge will be the scaling up of GMP-grade $^{161}$Tb production to meet potential clinical demand if the therapy proves successful and gains widespread adoption. Ensuring a reliable and cost-effective supply chain for this specialized radionuclide is crucial.[14]
Patient Selection and Dosimetry: Further refinement of patient selection criteria, potentially utilizing advanced molecular imaging techniques or biomarkers, could help identify individuals most likely to benefit from this therapy. Continued development of patient-specific dosimetry methods will also be important for optimizing treatment plans.
Regulatory Approval: Navigating the regulatory pathways with agencies like the FDA and EMA will require a comprehensive data package demonstrating a favorable benefit-risk profile.

While the early data for 161Tb-DOTA-LM3 are exceptionally promising, its journey from an investigational agent to a standard clinical treatment requires rigorous further evaluation. The initial proof-of-concept and favorable dosimetry observed in the first human studies [4] are significant steps. However, demonstrating a clear and statistically significant clinical benefit over established therapies in well-designed Phase II and III trials will be the ultimate determinant of its future role. Addressing the logistical and economic challenges associated with the production and supply of $^{161}$Tb will also be critical for its broader clinical integration. If these hurdles can be successfully overcome, 161Tb-DOTA-LM3 stands to offer a new and more effective therapeutic option for patients battling neuroendocrine tumors.

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161Tb-DOTA-LM3 Advanced Drug Monograph

Generic Name