Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Efficacy of actinium-225-labeled fully human anti-MUC-16 radioimmunoconjugate against MUC-16-positive ovarian and pancreatic ductal adenocarcinoma xenograft models.
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Babeker Hanan, Nwangele Emmanuel, Monzer Alissar, Pougoue Ketchemen Jessica, Bato Katrina E, Njotu Fabrice N, Tikum Anjong F, Mercado Therese, Doroudi Alireza, Torlakovic Emina, Gordon John R, Uppalapati Maruti, Fonge Humphrey
Аннотация
PURPOSE: MUC-16-targeted antibodies can deliver contrast agents (diagnostic) and/or cytotoxic payloads (therapy) to the tumor site. MUC-16 is overexpressed in 80% of epithelial ovarian cancer (EOC) and 65% of pancreatic ductal adenocarcinomas (PDAC). We previously developed a fully human antibody against MUC-16 (M16AB) and demonstrated the utility of [89Zr]Zr-DFO-M16AB as a PET imaging agent. Here, we developed [225Ac]Ac-Macropa-M16AB radioimmunoconjugate (RIC) and studied its efficacy against MUC-16-positive EOC and PDAC xenografts.
EXPERIMENTAL DESIGN: [225Ac]Ac-Macropa-M16AB was characterized in vitro. The pharmacokinetics, biodistribution, hematological safety and dosimetry of [225Ac]Ac-Macropa-M16AB were studied in healthy mice. The efficacy of two doses (13 or 18.6 kBq) [225Ac]Ac-Macropa-M16AB administered at 10 days apart was evaluated in MUC-16-expressing cell line-derived xenograft (CDX) SW1990 and mice bearing PDAC and EOC patient-derived xenografts (PDX) with varying MUC-16 expression levels.
RESULTS: In SW1990 CDX models [225Ac]Ac-Macropa-M16AB induced complete remission (CR) in 16.7% of mice, while the remaining 83.3% exhibited durable tumor growth suppression for ≥ 50 days, whereas all control animals progressed rapidly. [225Ac]Ac-Macropa-M16AB treatment resulted in 100% sustained CRs in high and medium-MUC16-expressing EOC and PDAC PDXs. While in the low MUC-16 expressing EOC PDX, the treatment demonstrated tumor growth inhibition and prolonged survival. [225Ac]Ac-Macropa-M16AB (3 x 15 kBq) administered in naive mice, 10-d apart was tolerated biochemically and haematologically, with only mild, dose-dependent hepatic and splenic changes observed on histopathology.
CONCLUSION: The effectiveness of[225Ac]Ac-Macropa-M16AB which is dependent on the expression levels of MUC-16 indicates potential benefits for EOC and PDAC patients when translated in clinical trials.
EXPERIMENTAL DESIGN: [225Ac]Ac-Macropa-M16AB was characterized in vitro. The pharmacokinetics, biodistribution, hematological safety and dosimetry of [225Ac]Ac-Macropa-M16AB were studied in healthy mice. The efficacy of two doses (13 or 18.6 kBq) [225Ac]Ac-Macropa-M16AB administered at 10 days apart was evaluated in MUC-16-expressing cell line-derived xenograft (CDX) SW1990 and mice bearing PDAC and EOC patient-derived xenografts (PDX) with varying MUC-16 expression levels.
RESULTS: In SW1990 CDX models [225Ac]Ac-Macropa-M16AB induced complete remission (CR) in 16.7% of mice, while the remaining 83.3% exhibited durable tumor growth suppression for ≥ 50 days, whereas all control animals progressed rapidly. [225Ac]Ac-Macropa-M16AB treatment resulted in 100% sustained CRs in high and medium-MUC16-expressing EOC and PDAC PDXs. While in the low MUC-16 expressing EOC PDX, the treatment demonstrated tumor growth inhibition and prolonged survival. [225Ac]Ac-Macropa-M16AB (3 x 15 kBq) administered in naive mice, 10-d apart was tolerated biochemically and haematologically, with only mild, dose-dependent hepatic and splenic changes observed on histopathology.
CONCLUSION: The effectiveness of[225Ac]Ac-Macropa-M16AB which is dependent on the expression levels of MUC-16 indicates potential benefits for EOC and PDAC patients when translated in clinical trials.