Ac-225 rosopatamab tetraxetan

Overview

Ac-225 rosopatamab tetraxetan (also known as 225Ac‑J591; CONV01‑α) is a PSMA‑targeted radiopharmaceutical therapy that couples the humanized anti‑PSMA monoclonal antibody rosopatamab (J591) to the alpha‑emitter actinium‑225 via the DOTA (tetraxetan) chelator. It is being developed primarily for metastatic castration‑resistant prostate cancer (mCRPC). Early phase clinical studies have reported antitumor activity as monotherapy (single dose and fractionated regimens) and in combination with 177Lu‑PSMA‑I&T. A company‑sponsored phase II program (CONVERGE‑01) began enrollment in August 2024. (ascopubs.org)

Mechanism of action

• Target: Prostate‑specific membrane antigen (PSMA, FOLH1) expressed on most prostate cancers. Rosopatamab is a humanized IgG1 mAb directed to an extracellular PSMA epitope. (drugs.ncats.io)
• Payload: Actinium‑225 emits high‑linear‑energy‑transfer alpha particles with short path length, causing clustered DNA double‑strand breaks in PSMA‑expressing tumor cells following antibody‑mediated binding and internalization. Antibody targeting yields a biodistribution distinct from small‑molecule PSMA ligands, with relatively less uptake in salivary glands, kidneys, and small bowel. (ascopubs.org)

Efficacy

Monotherapy (first‑in‑human, single dose; Phase I)
- 32 patients with pretreated, progressive mCRPC received a single infusion across 7 dose levels (up to 93.3 kBq/kg). Any‑time PSA50 decline occurred in 46.9% (confirmed PSA50 in 34.4%); protocol‑defined CTC response in 59.1%. The RP2D was the highest tested dose (93.3 kBq/kg). (ascopubs.org)

Monotherapy (fractionated dosing; Phase I dose‑escalation)
- Fractionated single‑cycle dosing on Day 1 and Day 15 in predominantly 177Lu‑naïve mCRPC showed PSA declines in 95–96% of evaluable patients; PSA50 in 67–70%; PSA90 in 26–37%. (aacrjournals.org)

Combination with 177Lu‑PSMA‑I&T (PNT2002) (Phase I, mature follow‑up, ASCO GU 2025)
- 18 patients received 177Lu‑PSMA‑I&T (6.8 GBq) plus 225Ac‑J591 (30, 35, or 40 kBq/kg) for up to two doses eight weeks apart. PSA declines occurred in 94% (PSA50 in 64%). Median biochemical PFS was 7.3 months; median OS was 29.8 months with 10/18 alive at submission. RP2D for 225Ac‑J591 in the combo was 35 kBq/kg. (ascopubs.org)

Ongoing development
- CONVERGE‑01 (Phase II, industry‑sponsored): Three‑part study assessing biodistribution/dosimetry and evaluating single‑cycle, two‑fraction CONV01‑α monotherapy; primary efficacy endpoint includes PSA50 response. Enrollment began August 2024 (NCT06549465). (ascopubs.org)

Safety

Across studies, the most frequent treatment‑emergent adverse events were hematologic (thrombocytopenia, anemia, neutropenia), generally correlating with administered activity; non‑hematologic events were typically low‑grade (fatigue, nausea, pain flare). Xerostomia has been reported but was mostly grade 1–2, consistent with the antibody’s limited salivary gland uptake compared with small‑molecule PSMA ligands. In the single‑dose phase I study (n=32), dose‑limiting toxicity was uncommon and the MTD was not reached. In the fractionated phase I, grade 4 thrombocytopenia occurred in 13% with other adverse events grade ≤3. In the 177Lu‑PSMA‑I&T combination phase I, grade 3 thrombocytopenia and anemia each occurred in 17%; no new safety signals emerged with longer follow‑up, and high‑grade events were rare. (ascopubs.org)

Further reading

• JCO (2024): First‑in‑human phase I dose‑escalation of single‑dose 225Ac‑J591 in mCRPC. (ascopubs.org)
• Cancer Research (AACR 2023): Phase I fractionated‑dose 225Ac‑J591 (oral presentation abstract). (aacrjournals.org)
• JCO (ASCO GU 2025): Mature phase 1 follow‑up of 225Ac‑J591 plus 177Lu‑PSMA‑I&T. (ascopubs.org)
• JCO (ASCO GU 2025, Trials‑in‑Progress): CONVERGE‑01 phase II of Ac‑225 rosopatamab tetraxetan (CONV01‑α). (ascopubs.org)
• JCO (ASCO 2022, TPS): Study rationale for combining PSMA‑targeted antibody alpha‑therapy with small‑molecule beta‑therapy; biodistribution differences. (ascopubs.org)
• NCATS Inxight/UNII entries for rosopatamab and rosopatamab tetraxetan (INN background). (drugs.ncats.io)

Notes: Efficacy data are from early phase studies in heavily pretreated mCRPC and use PSA‑based endpoints with limited radiographic response reporting; randomized trials are ongoing to define clinical benefit more robustly. (ascopubs.org)

Last updated: Oct 2025