Engineering of a Fully Human Anti-MUC-16 Antibody and Evaluation as a PET Imaging Agent.
Hanan BabekerJessica Pougoue KetchemenArunkumar Annan SudarsanSamitha AndrahennadiAnjong Florence TikumAnand Krishnan NambisanHumphrey FongeMaruti UppalapatiPublished in: Pharmaceutics (2022)
Antibodies that recognize cancer biomarkers, such as MUC16, can be used as vehicles to deliver contrast agents (imaging) or cytotoxic payloads (therapy) to the site of tumors. MUC16 is overexpressed in 80% of epithelial ovarian cancer (EOC) and 65% of pancreatic ductal adenocarcinomas (PDAC), where effective 'theranostic' probes are much needed. This work aims to develop fully human antibodies against MUC16 and evaluate them as potential immuno-PET imaging probes for detecting ovarian and pancreatic cancers. We developed a fully human monoclonal antibody, M16Ab, against MUC16 using phage display. M16Ab was conjugated with p-SCN-Bn-DFO and radiolabeled with 89 Zr. 89 Zr-DFO-M16Ab was then evaluated for binding specificity and affinity using flow cytometry. In vivo evaluation of 89 Zr-DFO-M16Ab was performed by microPET/CT imaging at different time points at 24-120 h post injection (p.i.) and ex vivo biodistribution studies in mice bearing MUC16-expressing OVCAR3, SKOV3 (ovarian) and SW1990 (pancreatic) xenografts. 89 Zr-DFO-M16Ab bound specifically to MUC16-expressing cancer cells with an EC 50 of 10nM. 89 Zr-DFO-M16Ab was stable in serum and showed specific uptake and retention in tumor xenografts even after 120 h p.i. (microPET/CT) with tumor-to-blood ratios > 43 for the SW1990 xenograft. Specific tumor uptake was observed for SW1990/OVCAR3 xenografts but not in MUC16-negative SKOV3 xenografts. Pharmacokinetic study shows a relatively short distribution (t 1/2α ) and elimination half-life (t 1/2ß ) of 4.4 h and 99 h, respectively. In summary, 89 Zr-DFO-M16Ab is an effective non-invasive imaging probe for ovarian and pancreatic cancers and shows promise for further development of theranostic radiopharmaceuticals.
Keyphrases
- pet imaging
- positron emission tomography
- endothelial cells
- fluorescence imaging
- photodynamic therapy
- high resolution
- computed tomography
- monoclonal antibody
- flow cytometry
- induced pluripotent stem cells
- small molecule
- living cells
- contrast enhanced
- pseudomonas aeruginosa
- magnetic resonance
- cystic fibrosis
- insulin resistance
- young adults
- skeletal muscle
- big data
- squamous cell
- fluorescent probe
- mass spectrometry
- deep learning
- cell therapy
- clinical evaluation