基于²¹²Pb的CEA预靶向放射免疫治疗在免疫缺陷和人源化小鼠模型中展现出肿瘤靶向和强效TGI,为mCRC的FIH研究提供依据

Background: Alpha particles (alpha) are exceptionally cytotoxic, inducing complex DNA damage and bystander effects. Targeted alpha-therapy demonstrated a favorable therapeutic index (TI) in certain cancers. To improve the TI and expand to other indications, we developed a 212 Pb-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 212 Pb-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 212 Pb-DOTAM. While unbound 212 Pb-DOTAM undergoes rapid renal clearance, 212 Pb-DOTAM captured by the SPLIT Abs leads to alpha 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 212 Pb-DOTAM (20 µCi) on day 8. Results: Average 212 Pb 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 203 Pb-DOTAM as a surrogate for therapeutic 212 Pb-DOTAM tumor uptake and healthy tissue distribution, SPLIT Ab pharmacokinetics, and tumor CEA expression to inform optimal SPLIT Ab dosing and interval to 212 Pb-DOTAM, before initiating the 212 Pb-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.