Radiopharmacologic screening of antibodies to the unshed ectodomain of MUC16 in ovarian cancer identifies a lead candidate for clinical translation

Nemieboka, Brandon; Sharma, Sai Kiran; Rao, Thapi D.; Edwards, Kimberly J.; Su, Yan; Wang, Pei; Ragupathi, Ashwin; Piersigilli, Alessandra; Spriggs, David R.; Lewis, Jason S.

doi:10.1016/j.nucmedbio.2020.04.006

Cited by 5 publications

(7 citation statements)

References 21 publications

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“…Flow cytometry revealed strong binding of muAR9.6 to MUC16-positive OVCAR3 cells as well as  more surprisingly  some binding to SKOV3 cells. The latter are considered MUC16-negative, and we have previously not observed binding of other MUC16-targeting antibodies such as B43.13 and 4H11 to SKOV3 cells (24,25,33,34). However, Reinartz et al have shown that SKOV3 cells have very low levels of MUC16 transcript (mRNA), and though they reported no binding of anti-CA125 antibodies to SKOV3 cells, Felder et al reported marginal binding of OC125-like MUC16-binding antibodies to SKOV3 cells via flow cytometry.…”

Section: Discussionmentioning

confidence: 93%

“…The therapeutic mechanism of muAR9.6 distinguishes it from other MUC16-targeted antibodies, including those reported from our laboratories (10,13,15,16,24,25,31,32). Motivated by its novelty, we set out to validate the in vitro cell binding of muAR9.6 and explore the in vivo behavior of a 89 Zr-labeled variant of the antibody in preclinical tumor models.…”

Section: Discussionmentioning

confidence: 99%

“…The vast majority of MUC16-targeted antibodies bind CA125 epitopes in the SEA/tandem repeat region (10,20) or the unshed carboxy-terminus domain (13,21,22). To date, anti-MUC16 antibodies have mostly been harnessed as vectors to deliver toxic payloads, radionuclides, or fluorophores (12,(23)(24)(25)(26). More recently, a new class of MUC16-targeted antibodies that interact with the N-or O-glycosylation sites on MUC16 have emerged and exert a therapeutic effect by abrogating the downstream pro-oncogenic signaling of cancer cells (10,15).…”

Section: Introductionmentioning

confidence: 99%

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ImmunoPET of Ovarian and Pancreatic Cancer with AR9.6, a Novel MUC16-Targeted Therapeutic Antibody

Sharma

Mack

Piersigilli

et al. 2021

Clinical Cancer Research

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In recent years, proteins with aberrant glycosylation patterns have emerged as therapeutic targets in oncology. Along these lines, MUC16 glycoforms have been implicated in the oncogenesis and metastatic progression of high-grade serous ovarian cancer (HGSOC) and pancreatic ductal adenocarcinoma (PDAC). AR9.6 is a therapeutic mAb that binds to MUC16, interferes with the interaction of MUC16 with ErbB receptors on the surface of cancer cells, and thereby attenuates the activation of downstream oncogenic signaling pathways. Here, we report the in vitro, ex vivo, and in vivo validation of [ 89 Zr]Zr-DFO-muAR9.6 and [ 89 Zr]Zr-DFO-huAR9.6 in murine models of MUC16-positive HGSOC and PDAC. Both radioimmunoconjugates displayed excellent tumor-targeting properties in vivo, ultimatelyResearch.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ImmunoPET of Ovarian and Pancreatic Cancer with AR9.6, a Novel MUC16-Targeted Therapeutic Antibody

Sharma

Mack

Piersigilli

et al. 2021

Clinical Cancer Research

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“…Several MUC16 antibodies of murine origin have been generated previously and some of these antibodies have been humanized for development as antibody-drug conjugates (ADCs) or as immuno-PET imaging probes [19][20][21][22][23]. Sharma et al [24] reported the development of a 89 Zr-labeled PET probe using a murine antibody B43.13 (oregovomab), while Olson et al [25] reported the evaluation of a murine antibody AR9.6 labeled with IRDye800CW for image-guided surgery.…”

Section: Introductionmentioning

confidence: 99%

Engineering of a Fully Human Anti-MUC-16 Antibody and Evaluation as a PET Imaging Agent

et al. 2022

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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 89Zr. 89Zr-DFO-M16Ab was then evaluated for binding specificity and affinity using flow cytometry. In vivo evaluation of 89Zr-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. 89Zr-DFO-M16Ab bound specifically to MUC16-expressing cancer cells with an EC50 of 10nM. 89Zr-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 (t1/2α) and elimination half-life (t1/2ß) of 4.4 h and 99 h, respectively. In summary, 89Zr-DFO-M16Ab is an effective non-invasive imaging probe for ovarian and pancreatic cancers and shows promise for further development of theranostic radiopharmaceuticals.

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“…Furthermore, [ 89 Zr]Zr-oregovomab detected histologically-confirmed lymph node involvement ( 368 ). The newer generation of Abs targeting MUC16 showed superior imaging characteristics ( 38 , 369 ). Additionally, an 89 Zr-labeled anti-MUC1 or CA 15-3 also showed proper performance in vivo ( 37 ).…”

Section: Immunopet In Different Malignanciesmentioning

confidence: 99%

ImmunoPET: Antibody-Based PET Imaging in Solid Tumors

et al. 2022

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Immuno-positron emission tomography (immunoPET) is a molecular imaging modality combining the high sensitivity of PET with the specific targeting ability of monoclonal antibodies. Various radioimmunotracers have been successfully developed to target a broad spectrum of molecules expressed by malignant cells or tumor microenvironments. Only a few are translated into clinical studies and barely into clinical practices. Some drawbacks include slow radioimmunotracer kinetics, high physiologic uptake in lymphoid organs, and heterogeneous activity in tumoral lesions. Measures are taken to overcome the disadvantages, and new tracers are being developed. In this review, we aim to mention the fundamental components of immunoPET imaging, explore the groundbreaking success achieved using this new technique, and review different radioimmunotracers employed in various solid tumors to elaborate on this relatively new imaging modality.

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Radiopharmacologic screening of antibodies to the unshed ectodomain of MUC16 in ovarian cancer identifies a lead candidate for clinical translation

Cited by 5 publications

References 21 publications

ImmunoPET of Ovarian and Pancreatic Cancer with AR9.6, a Novel MUC16-Targeted Therapeutic Antibody

ImmunoPET of Ovarian and Pancreatic Cancer with AR9.6, a Novel MUC16-Targeted Therapeutic Antibody

Engineering of a Fully Human Anti-MUC-16 Antibody and Evaluation as a PET Imaging Agent

ImmunoPET: Antibody-Based PET Imaging in Solid Tumors

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