What question did this study set out to answer?

To evaluate the efficacy and safety of 212Pb-based CEA pretargeted radioimmunotherapy (CEA-PRIT 2.0) in mouse models of metastatic colorectal cancer.

April 5, 2026

Abstract 7203: 212Pb-based CEA pretargeted radioimmunotherapy demonstrates tumor targeting and potent TGI in immunodeficient and humanized mouse models, informing a FIH study in mCRC

Key Points

To evaluate the efficacy and safety of 212Pb-based CEA pretargeted radioimmunotherapy (CEA-PRIT 2.0) in mouse models of metastatic colorectal cancer.
Assessed tumor growth inhibition (TGI), biodistribution, and tolerability in three CEA-expressing human xenograft models.
Used SCID mice with BxPC3 and LS174T tumors for up to 5 treatment cycles, and BRGS-CD47 mice for 3 cycles.
Administered SPLIT Abs followed by 212Pb-DOTAM to measure tumor uptake and systemic effects.
Average tumor uptake of 212Pb was 10-43% of injected activity per gram of tissue at 24 hours.
Demonstrated potent TGI in LS174T model at lowest doses of SPLIT Abs.
Managed body weight loss, with variable effects across different models and suggesting strain-specific responses.

Abstract

Abstract Background: Alpha particles (α) are exceptionally cytotoxic, inducing complex DNA damage and bystander effects. Targeted α-therapy demonstrated a favorable therapeutic index (TI) in certain cancers. To improve the TI and expand to other indications, we developed a 212Pb-based carcinoembryonic antigen-related cell adhesion molecule 5 pretargeted radioimmunotherapy (CEA-PRIT 2.0), involving two complementary SeParated v-domains LInkage Technology antibodies (SPLIT Abs) and 212Pb-DOTAM. Each CEA-targeted SPLIT Ab carries half of a DOTAM binding v-domain that, when combined upon target binding, forms concentration-dependent stable complexes with 212Pb-DOTAM. While unbound 212Pb-DOTAM undergoes rapid renal clearance, 212Pb-DOTAM captured by the SPLIT Abs leads to α emission at CEA-expressing cells with minimal systemic irradiation. Here, we report key preclinical data informing a planned first-in-human (FIH) CEA-PRIT 2.0 study in metastatic colorectal cancer (mCRC) patients. Methods: We assessed CEA-PRIT 2.0-induced tumor growth inhibition (TGI), biodistribution, and tolerability in 3 CEA-expressing human xenograft models. SCID mice bearing BxPC3 (pancreatic) or LS174T (colorectal) tumors received up to 5 treatment cycles, and BRGS-CD47 mice (humanized and non-humanized) bearing HPAF-II (pancreatic) tumors received up to 3 cycles. Each cycle consisted of the two SPLIT Abs (1-5 mg/kg each) given on day 1 to allow for accumulation on CEA-expressing cells before giving 212Pb-DOTAM (20 µCi) on day 8. Results: Average 212Pb tumor uptake in all models was 10-43% injected activity per gram of tissue (IA/g) at 24 h, with low blood and kidney retention (3% IA/g). In the BxPC3 model, TGI was SPLIT Ab dose-dependent, while the LS174T model showed potent TGI already at the lowest dose (1 mg/kg). The SPLIT Ab dose-dependence of the TGI in the HPAF-II model was abrogated in huBRGS-CD47, suggesting secondary immune responses contribute to the therapeutic effect.Manageable body weight (BW) loss was observed in the SCID BxPC3 model. More pronounced BW loss in LS174T (SCID) and HPAF-II (BRGS-CD47/huBRGS-CD47) models was observed, but minimal BW gain or actual BW loss in controls suggests tumor burden toxicity or strain-specific sensitivity were contributing factors.Utilizing the preclinical data, we designed a FIH study, starting with 203Pb-DOTAM as a surrogate for therapeutic 212Pb-DOTAM tumor uptake and healthy tissue distribution, SPLIT Ab pharmacokinetics, and tumor CEA expression to inform optimal SPLIT Ab dosing and interval to 212Pb-DOTAM, before initiating the 212Pb-DOTAM activity escalation and potential cancer immunotherapy combinations. Conclusions: CEA-PRIT 2.0 showed favorable tumor-to-healthy tissue radiation exposure and potent TGI with a favorable toxicity profile. A FIH study in mCRC is planned in H1 2026. Citation Format: Sofia H. Frost, Alexandre Pichard, Annabelle Mouchotte, Agnès Colmont, Sara Colombetti, Alexander Haas, Hans Peter Grimm, Birgit Kittel, Stephen Fowler, Bernhard Reis, Vincent Wolowski, Uta Sweere, Michael Hettich, Wolfgang Jacob, Frederic Prince, Christian Klein, Pablo Umana, Julien Torgue, Axel Boehnke. 212Pb-based CEA pretargeted radioimmunotherapy demonstrates tumor targeting and potent TGI in immunodeficient and humanized mouse models, informing a FIH study in mCRC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7203.

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