Background/Objectives: A mouse antibody directed against truncated Annexin A1 showed high tumor retention in pre-clinical cancer models and was approved by the National Cancer Institute Experimental Therapeutics (NExT) program for humanization and large batch cGMP production for toxicology and clinical trials. In this process, a contractor for Leidos accidentally produced a mutated version of humanized AnnA1 (hAnnA1-mut) with a single nucleotide deletion in the terminal Fc coding region that increased the translated size by eight amino acids with random alterations in the final twenty-four amino acids. We investigated the tissue distribution of hAnnA1-mut, hAnnA1, mAnnA1, and isotope-matched human IgG1 under various injection and conjugation conditions with C57BL/6, FVB, and BALB/c nude mice strains. Methods: Biodistribution studies were performed 24 h after injection of Tc-99m-HYNIC radiolabeled antibodies (purity > 98%). Non-reducing gel electrophoresis studies were conducted with IR680 labeled antibodies incubated with various mouse sera. Results: Our results showed that Tc-99m-HYNIC-hAnnA1 had low spleen and liver retention not statistically different from Tc-99m-HYNIC-IgG1 and Tc-99m-HYNIC-mAnnA1, with corresponding higher blood levels; however, Tc-99m-HYNIC-hAnnA1-mut had high levels in the spleen and liver with differences identified among the mouse strains, radiolabeling conditions, and injection routes. Histopathology showed no morphological change in the liver or spleen from any conditions. Gel electrophoresis showed an upward shift of hAnnA1-mut, consistent with the binding of blood serum protein. Conclusions: The changes in the Fc region of hAnnA1-mut led to higher liver and spleen uptake, suggesting the antibody’s recognition by the innate immune system (likely complement protein binding) and subsequent clearance. Future clinical translation using hAnnA1 and other antibodies needs to limit protein modifications that could drastically reduce blood clearance.

Ovarian cancer (OC) is frequently diagnosed at an advanced stage and characterized by high rates of recurrence despite aggressive cytoreductive surgery and chemotherapy. Relapse is driven by microscopic residual tumors that are disseminated most often throughout the peritoneal cavity, posing significant challenges with conventional systemic therapy. Targeted alpha-particle therapy (TAT) combines molecular targeting with alpha-emitting radionuclides to deliver highly potent and localized cellular damage, uniquely suited for the eradication of small OC tumor clusters within the peritoneal cavity. We conducted an extensive literature search for clinical trials (clinicaltrials.gov) and pre-clinical studies (PubMed, Scopus, Google Scholar) between September 2025 and November 2025. Peer-reviewed articles published in English over the past 20 years that used OC mouse models with reported treatment data were included. Review articles without original data and clinical trials that have been terminated or withdrawn were excluded. In this review, we (1) summarize the biological and physical rationale supporting the use of TAT in OC, (2) discuss the relevant molecular and immunological anti-tumor mechanisms, and (3) critically evaluate early treatment outcomes of 19 pre-clinical and four clinical studies with respect to efficacy, safety, and feasibility. Despite the progress and promising survival outcomes, several challenges remain, including heterogeneous antigen expression, delivery and retention within the peritoneal cavity, off-target toxicity, radiation resistance, radionuclide availability, dosimetry uncertainties, and limitations in clinical trial design. We highlight future directions to overcome these barriers and the continued multidisciplinary efforts essential to translate TAT into effective clinical strategies to treat advanced stages of OC and other solid tumors resistant to conventional treatment. This work was supported with funding available to Kurt R. Zinn as the Hickman Family Endowed Chair in Oncology at Michigan State University.