UPDATE: OncoACP3‑DOTA, First‑in‑Human Therapeutic Signal Beyond PSMA

OncoACP3‑DOTA is a small‑molecule ligand directed at prostatic acid phosphatase (ACP3, also historically called PAP), a membrane‑bound phosphatase that is highly specific to the prostate, with only weak expression in normal tissues such as kidney. Preclinical work showed that ACP3 is retained in many prostate tumors, including lesions with low or absent PSMA expression, and that a gallium‑68‑labeled version, ⁶⁸Ga‑OncoACP3‑DOTA, yields intense tumor uptake while largely avoiding salivary glands and kidneys. This has now been translated into a dedicated ACP3‑based radiopharmaceutical pair, with a 68Ga‑labeled version for PET imaging and a 225Ac‑labeled version for RLT.

In a 25‑patient cohort trial, ⁶⁸Ga‑OncoACP3‑DOTA PET showed strong tumor uptake with markedly lower uptake in salivary glands, lacrimal glands, kidney, liver, and spleen compared with standard PSMA‑PET. In some patients, the ACP3 scan changed detection or intensity of lesions, and several men had adjustments in management as a result.

Against this background, a separate group of four heavily pretreated men who had already received multiple cycles of PSMA‑targeted radioligand therapy and had progressed despite treatment, mostly with 177Lu‑PSMA‑617 (Pluvicto),  were treated under compassionate‑use conditions with 177Lu‑OncoACP3‑DOTA.

Tumor‑associated radioactivity remained nearly stable between 2 days and 7–8 days after injection in many lesions, with effective retention time approximating the physical decay of lutetium‑177. This suggests unusually long on‑target binding compared with many existing beta‑emitter RLTs, which typically show faster washout from tumors.
(Note: In this specific case, the ligand was paired with lutetium‑177, not with actinium‑225, which suggests it is compatible with multiple radio‑emitter backbones and can be adapted to other beta or even alpha‑emitter isotopes in future development.)

Crucially, salivary‑gland uptake remained negligible throughout the post‑therapy SPECT series, reinforcing the imaging‑based observation that this ligand largely avoids both salivary and lacrimal tissue. Organ‑dose estimates indicated that bone‑marrow and other organ exposures were broadly in the same range as contemporary PSMA‑617 experience, with no overt signs of excess marrow toxicity in this small group. One heavily pretreated man received three cycles of 177Lu‑OncoACP3‑DOTA after many prior PSMA‑RLT cycles and achieved a deep PSA decline that lasted more than 200 days before the marker returned to baseline. The other two patients with extensive liver‑dominant disease progressed despite treatment, which is consistent with the known challenges of eradicating liver‑only metastases even with potent radiopharmaceuticals.

Several important caveats apply. The cohort is very small, the patients are all in late‑line, PSMA‑exposed, PSMA‑progressed disease, and the data come from a compassionate‑use setting rather than a controlled trial, so selection bias and uncontrolled confounding are inevitable. There is no randomized head‑to‑head comparison with PSMA‑RLT or other standards, and longer‑term safety, optimal sequencing, and dose‑finding remain open questions. Nevertheless, this is the first articulated clinical therapeutic experience with OncoACP3‑DOTA in humans, combining high tumor uptake, low off‑target exposure, and measurable PSA responses in patients who had already exhausted PSMA‑targeted therapy.

Source.