Nendratareotide Uzatansine
An octreotate-like peptide that carries the cell poison DM1 into tumours bearing somatostatin receptor 2
Nendratareotide uzatansine (PEN-221) joins a small somatostatin-like peptide to DM1, a maytansinoid that blocks cell division, so that tumours rich in somatostatin receptor 2 pull the drug inside. It shrank tumours in mice. In its one trial, 89 people with neuroendocrine tumours or small-cell lung cancer received it into a vein every three weeks; the posted results show stable disease in many but no confirmed tumour responses, and no journal has published the trial. It is approved nowhere.
Used in human trials: 1 to 25 mg, Every 3 weeks, Intravenous infusion (Phase 1 dose escalation, SSTR2-rich NET or SCLC (23 patients)) Details ↓
Recommended Dosing
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
Nendratareotide uzatansine is a small anticancer molecule built from two parts, and its international name spells them out. The first, nendratareotide, is an eight-residue peptide closely related to octreotate, the somatostatin look-alike used in imaging and radiation treatments; FDA's substance registry gives it as D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Cys-NH2, with a disulfide ring between the second and seventh residues. The second, uzatansine, is the maytansinoid DM1, a plant-derived poison that stops cells from building the microtubules they need to divide. A disulfide link joins DM1 to the peptide's last cysteine. The whole molecule weighs about 1,787 daltons. Tarveda Therapeutics developed it under the code PEN-221 and its own papers call it a miniaturized drug conjugate, small next to the antibody-drug conjugates that carry DM1 on a whole antibody.
The target is somatostatin receptor 2 (SSTR2). Many neuroendocrine tumours, and a share of small-cell lung cancers, carry far more of it than normal tissue, and when an agonist peptide binds, the receptor is pulled into the cell. Octreotide and lanreotide use that receptor to calm hormone release and slow tumour growth, and lutetium-177 dotatate uses it to deliver radiation. PEN-221 uses it to deliver chemotherapy. In the developers' laboratory work it killed SSTR2-bearing cells at low concentrations, lost most of that potency when the receptor was blocked, built up in SSTR2-rich tumours in mice while leaving the blood quickly, and shrank several kinds of xenograft tumour. Outside groups have since used it as an SSTR2 tool, in nasopharyngeal cancer models and as an off switch for engineered T cells in mice.
No journal paper reports what nendratareotide uzatansine did in people. Its only trial, NCT02936323, was a phase 1/2a study that Tarveda ran at 13 sites in the United States and United Kingdom from December 2016 to February 2021 in 89 adults whose tumours showed SSTR2 on a somatostatin-receptor scan. The 23 people in the dose-finding part received flat doses of 1 to 25 mg into a vein every three weeks; two of the three given 25 mg had dose-limiting side effects, and 18 mg was set as the highest tolerated dose (NCT02936323; 2018 ASCO abstract, doi:10.1200/JCO.2018.36.15_suppl.4097). The expansion part then treated 66 more people, 32 with midgut neuroendocrine tumours, 15 with pancreatic ones and 19 with small-cell lung cancer, and settled on 8.8 mg per square metre of body surface (NCT02936323). The results were posted to ClinicalTrials.gov in December 2021.
Those posted results show no tumour shrinking enough to count as a response under the standard tumour-measurement rules in any expansion cohort. What they show instead is disease that stopped growing for a while in some groups: 23 of 26 evaluable people with midgut tumours had stable disease or better, with a median of 9.0 months before progression, against 6 of 12 with pancreatic tumours (3.2 months). In small-cell lung cancer 3 of 12 had stable disease and none responded; the median time to progression was 1.4 months and median survival 3.9 months (NCT02936323). The study had no comparison group, and midgut neuroendocrine tumours often grow slowly on their own, so stable disease in a single-arm trial says little about benefit. Side effects were common: nausea, fatigue and diarrhoea each affected about half of the 89 patients, 35 had a serious adverse event, and the registry lists four deaths from adverse events during treatment, two of them among expansion patients dosed above 8.8 mg per square metre.
No later trial has been registered. ChEMBL records a highest phase of 1, Drugs@FDA and the openFDA label endpoint hold nothing for it, and it is approved nowhere. It belongs with the other peptide-drug conjugates on this site as an example of the idea and of how hard the step to patients is; it is not a product anyone can obtain, and as a cytotoxic drug it would be given only by a cancer team.
At a Glance
Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.
Mechanism of Action
The design is a delivery system. The peptide finds and enters the tumour cell, the linker lets go inside, and the payload does the killing.
Pulled inside the cell
Agonist binding makes SSTR2 internalise, taking the conjugate with it. Its activity in cells fell about 90-fold when the receptor was blocked, which is how the developers showed that entry runs through the receptor (PMID 30735385).
A disulfide link that opens inside
DM1 is joined to the peptide's last cysteine through a disulfide bond (FDA GSRS UNII L8993M383E). Bonds of this kind are split in the reducing interior of cells, freeing the payload; the trial measured free DM1 in plasma alongside the intact conjugate (NCT02936323).
DM1 stops cell division
The payload is a microtubule-targeting maytansinoid (PMID 30735385). Treated tumours in mice showed more cells stuck in mitosis and more apoptosis, by phosphohistone H3 and cleaved caspase-3 staining (PMID 31649014).
Published Research
These five records are every PubMed paper on PEN-221, read from their abstracts on November 4, 2026. Two are the developer's laboratory and mouse studies, two are outside groups using it as an SSTR2 tool in rodents, and one is a 2026 review that names it. Three titles do not name the drug and are carded because their abstracts do. None is a human study: the trial in patients is known from its registry results and a 2018 meeting abstract, described in the overview and the dosing table. Studies of other SSTR2 drugs, radioligands or antibody conjugates of DM1 belong to those drugs.
Discovery: choosing the peptide, the attachment point and the payload
Tarveda's chemists compared several SSTR2-targeting peptides, places to attach the drug and cytotoxic payloads before settling on compound 22, PEN-221: DM1 joined to the side chain at the C-terminal end of Tyr-octreotate. In SSTR2-expressing cells it stopped growth at about 10 nM, and blocking the receptor made it roughly 90 times weaker, which points to receptor-driven uptake. In mice carrying SSTR2-rich xenografts it delivered high amounts of DM1 to the tumours and caused regressions in several models. The paper noted that human trials had begun. Company authors throughout.
Small-cell lung cancer cells and xenografts
A second Tarveda paper focused on small-cell lung cancer, where SSTR2 is often high and normal tissue carries little. In SSTR2-rich cells PEN-221 was taken inside and slowed proliferation only when the receptor was present. In mice with SSTR2-rich lung cancer xenografts it reached the tumour fast, left the plasma quickly and stayed in the tumour, raising markers of mitotic arrest (phosphohistone H3) and cell death (cleaved caspase-3). Several dosing schedules, some below the maximum tolerated dose, produced complete regressions. The authors argued that its small size lets it penetrate deep into tumours with little time in the blood.
Nasopharyngeal cancer: a target switched on by Epstein-Barr virus
An international team found high SSTR2 in more than 400 nasopharyngeal cancers and traced it to the Epstein-Barr virus protein LMP1 acting through NF-kB. In cell and rodent models they tested PEN-221 as the SSTR2-directed treatment and found it worked better than the approved SSTR2-binding drugs, which slow growth rather than kill cells. The human parts of the paper concern receptor levels, survival and gallium-68 PET imaging in patients, not PEN-221, which was not given to people here.
An off switch for engineered T cells in mice
Researchers at Weill Cornell gave CAR T cells the SSTR2 receptor so they could be tracked by imaging and, if needed, destroyed. Their cells, which also released interleukin-12, kept multiplying after clearing the tumour and made the mice ill. Treating the mice with PEN-221 cut the number of CAR T cells quickly, made the graft-versus-host reaction milder and lengthened survival. The point was a safety switch for cell therapy, using the conjugate as the tool rather than as a cancer drug.
Where chemotherapy and targeted payloads stand in lung neuroendocrine tumours
Italian oncologists reviewed the literature and trial registries on chemotherapy for lung neuroendocrine tumours. They describe old platinum and etoposide regimens as weak against well-differentiated carcinoids and temozolomide-based combinations as more promising, and they list peptide-drug conjugates, with PEN-221 as the example, beside antibody-drug conjugates and bispecific T-cell engagers as the direction the field is moving. They call for prospective trials.
Dosing Data
Nendratareotide uzatansine has no label. The rows below are the phase 1 doses reported in the trial's 2018 ASCO abstract, given as a one-hour infusion into a vein every three weeks (the infusion time is from the registry record). The expansion part later dosed by body surface area at 8.8 mg per square metre (NCT02936323); that figure is in the registry results only and is not tabled.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the trial's posted results on ClinicalTrials.gov (NCT02936323), counting all 89 patients, and its 2018 phase 1 abstract. No journal paper reports them.
Contraindications & Cautions
There is no label. The trial's entry rules show who was kept out (NCT02936323).
Legal Status
Nendratareotide uzatansine is an investigational drug that was never approved anywhere.
Frequently Asked Questions
?What is nendratareotide uzatansine?
A peptide-drug conjugate coded PEN-221: an eight-residue peptide related to octreotate, which binds somatostatin receptor 2, joined to DM1, a maytansinoid that stops cell division. The peptide is meant to carry the poison into tumour cells that carry the receptor.
?Did it work?
In mice it shrank SSTR2-rich tumours (PMIDs 30735385, 31649014). In its one trial in people no tumour shrank enough to count as a response; many people with midgut neuroendocrine tumours had stable disease for a median of nine months, but the trial had no comparison group, and in small-cell lung cancer the disease progressed fast (NCT02936323).
?How is it different from octreotide or lutetium-177 dotatate?
All three use somatostatin receptor 2. Octreotide is the peptide alone and slows hormone release and tumour growth. Lutetium-177 dotatate carries a radioactive atom. Nendratareotide uzatansine carries a chemotherapy drug instead, and its peptide ends in a cysteine that holds the drug.
?Why is there no human study card on this page?
Because the trial has not been published in a journal. Its results are on ClinicalTrials.gov and its phase 1 part in a 2018 ASCO abstract, and both are described on this page with their sources.
?Can anyone get it?
No. It is approved nowhere and no trial is recruiting. It is a cytotoxic cancer drug that was only ever given into a vein by trial staff.
References
- [pubmed] White BH, et al. "Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo." J Med Chem, 2019;62(5):2708-2719. PMID: 30735385.
- [pubmed] Whalen KA, et al. "Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer." Mol Cancer Ther, 2019;18(11):1926-1936. PMID: 31649014.
- [pubmed] Lechner M, et al. "Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy." Nat Commun, 2021;12(1):117. PMID: 33402692.
- [pubmed] Alcaina Y, et al. "SSTR2 as an anatomical imaging marker and a safety switch to monitor and manage CAR T cell toxicity." Sci Rep, 2022;12(1):20932. PMID: 36463361.
- [review] Laffi A, et al. "Redefining the Role of Chemotherapy and Targeted Cytotoxic Delivery in Lung Neuroendocrine Tumors." Thorac Cancer, 2026;17(16):e70376. PMID: 42592685.
- [clinical-trial] Johnson ML, Meyer T, Halperin DM, et al. "First in human phase 1/2a study of PEN-221 somatostatin analog (SSA)-DM1 conjugate for patients (PTS) with advanced neuroendocrine tumor (NET) or small cell lung cancer (SCLC): Phase 1 results." J Clin Oncol, 2018;36(15_suppl):4097. doi:10.1200/JCO.2018.36.15_suppl.4097 (2018 ASCO Annual Meeting abstract, not PubMed-indexed; read on ASCO's meeting site November 4, 2026).
- [registry] ClinicalTrials.gov NCT02936323, read November 4, 2026 with its posted results (first posted December 14, 2021): Tarveda Therapeutics' open-label phase 1/2a study of PEN-221 in somatostatin receptor 2-positive advanced cancers; 89 enrolled at 13 sites in the US and UK, December 2016 to February 2021, completed. Phase 1: 23 patients in seven cohorts given 1, 2, 4, 8, 12, 18 or 25 mg intravenously over one hour every 3 weeks; dose-limiting toxicities in 2 of 3 at 25 mg; maximum tolerated dose 18 mg. Phase 2a: 66 patients (32 midgut NET, 15 pancreatic NET, 19 SCLC), dose confirmed at 8.8 mg/m2. https://clinicaltrials.gov/study/NCT02936323
- [other] FDA Global Substance Registration System, Nendratareotide uzatansine, UNII L8993M383E (synonym PEN-221; INN 11298, CAS 1853254-97-3, NCI Thesaurus C131562), formula C83H109ClN14O20S4, molecular weight 1786.56, read November 4, 2026; its peptide part, nendratareotide, is UNII N3MT2V368J (INN 11297): D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-cysteinamide, cyclic (2-7) disulfide. https://gsrs.ncats.nih.gov/ginas/app/beta/substances/L8993M383E
- [other] ChEMBL molecule CHEMBL4650335 (NENDRATAREOTIDE UZATANSINE), read November 4, 2026: molecule type Protein, synonyms Nendratareotide uzatansine (INN) and PEN-221, INN stems -tansine and -tide; highest clinical phase recorded 1. https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL4650335/
- [other] US FDA, Drugs@FDA and the drug label endpoint (openFDA), searched November 4, 2026 for nendratareotide and PEN-221: no application and no label record.
Sources & Citations
The five studies carded above are every PubMed record on PEN-221 or nendratareotide, read from their abstracts on November 4, 2026. Structure and formula come from FDA's substance registry (UNII L8993M383E and N3MT2V368J); phase from ChEMBL (CHEMBL4650335); the trial design, doses, outcomes and side effects from ClinicalTrials.gov (NCT02936323, posted results) and the 2018 ASCO abstract; United States status from Drugs@FDA and openFDA, all read the same day. Grey Peptides sells nothing and links to no vendor.
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