Exploiting the MUC5AC Antigen for Noninvasive Identification of Pancreatic Cancer

Henry, Kelly E.; Shaffer, Travis M.; Mack, Kyeara N.; Ring, Janine; Ogirala, Anuja; Klein-Scory, Susanne; Eilert-Micus, Christina; Schmiegel, Wolff; Bracht, Thilo; Sitek, Barbara; Clyne, Marguerite; Reid, Colm J.; Sipos, Bence; Lewis, Jason S.; Kalthoff, Holger; Grimm, Jan

doi:10.2967/jnumed.120.256776

Cited by 5 publications

(5 citation statements)

References 31 publications

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“…Nonspecific binding to Fc receptors in the liver is common for radiolabeled full-length IgG antibodies because these antibodies still have an intact Fc region (36,37). Nonspecific uptake in these organs did not significantly affect tumor uptake; however, nonspecific uptake could potentially be blocked with the administration of an excess of unlabeled antibody before administration of its radiolabeled counterpart (38,39). Antibodies targeting shed antigen have been successfully used in the clinic for immuno-PET imaging with this approach (40).…”

Section: Discussionmentioning

confidence: 99%

Interrogating the Theranostic Capacity of a MUC16-Targeted Antibody for Ovarian Cancer

Mack,

Samuels,

Carter

et al. 2024

J Nucl Med

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Aberrantly expressed glycans on mucins such as mucin-16 (MUC16) are implicated in the biology that promotes ovarian cancer (OC) malignancy. Here, we investigated the theranostic potential of a humanized antibody, huAR9.6, targeting fully glycosylated and hypoglycosylated MUC16 isoforms. Methods: In vitro and in vivo targeting of the diagnostic radiotracer [ 89 Zr]Zr-DFO-huAR9.6 was investigated via binding experiments, immuno-PET imaging, and biodistribution studies on OC mouse models. Ovarian xenografts were used to determine the safety and efficacy of the therapeutic version, [ 177 Lu]Lu-CHX-A99-DTPA-huAR9.6. Results: In vivo uptake of [ 89 Zr]Zr-DFO-huAR9.6 supported in vitro-determined expression levels: high uptake in OVCAR3 and OVCAR4 tumors, low uptake in OVCAR5 tumors, and no uptake in OVCAR8 tumors. Accordingly, [ 177 Lu]Lu-CHX-A99-DTPA-huAR9.6 displayed strong antitumor effects in the OVCAR3 model and improved overall survival in the OVCAR3 and OVCAR5 models in comparison to the saline control. Hematologic toxicity was transient in both models. Conclusion: PET imaging of OC xenografts showed that [ 89 Zr]Zr-DFO-huAR9.6 delineated MUC16 expression levels, which correlated with in vitro results. Additionally, we showed that [ 177 Lu]Lu-CHX-A99-DTPA-huAR9.6 displayed strong antitumor effects in highly MUC16-expressing tumors. These findings demonstrate great potential for 89 Zr-and 177 Lu-labeled huAR9.6 as theranostic tools for the diagnosis and treatment of OC.

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Section: Discussionmentioning

confidence: 99%

Interrogating the Theranostic Capacity of a MUC16-Targeted Antibody for Ovarian Cancer

Mack,

Samuels,

Carter

et al. 2024

J Nucl Med

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“…MUC5AC and MUC5B have been found to play significant roles in asthma, chronic obstructive pulmonary disease, and pulmonary cystic fibrosis. In a healthy state, MUC5B is the major gelatinous mucin in the lung and is required for mucociliary clearance, while MUC5AC is a minor mucin in healthy lungs [14,15] . The results showed that MUC5AC in induced sputum and tissues of asthmatic patients was significantly higher than that of the control group, while MUC5B was significantly lower in asthmatic patients than in the control group.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance and Levels of NLRP3, MUC5AC, and MUC5B in Asthma

Yao

Tian

et al. 2023

JCNR

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Objective: To explore the role of NLRP3 in mucus hypersecretion in asthmatic patients. Methods: From January 2020 to June 2022, 90 patients with asthma and 60 healthy patients under the Department of Pulmonary and Critical Care Medicine of the First Affiliated Hospital of Xi’an Medical University were selected. Immunohistochemistry and enzyme-linked immunosorbent assay were performed. NLRP3 inflammasome and mucins MUC5AC and MUC5B levels in lung tissue and sputum were detected. Results: Compared to the healthy control group, the asthma group had significantly higher sputum MUC5A (20.12 ± 5 .07 versus 36.21 ± 6.13) and NLRP3 (72.31 ± 15.13 versus 119.21 ± 31.21) levels (P < 0.05) but lower MUC5B levels (1.35 ± 0.12 versus 0.53 ± 0.11, P < 0.05). Immunohistochemistry showed that NLRP3, MUC5AC, and MUC5B expressions were consistent with the sputum results. Conclusion: NLRP3 and MUC5AC levels are significantly increased in asthmatic patients, whereas MUC5B levels are reduced in these patients. They can be used as targets for the diagnosis and treatment of asthma.

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“…Kaur et al showed that serum MUC5AC levels aided in differentiating PDAC from chronic pancreatitis and benign pancreatic disease [ 24 ]. In addition to using fluorescent anti-MUC5AC antibodies to label PDAC, anti-MUC5AC antibodies have been used to image PDAC via PET-CT [ 25 ]. Nakata et al utilized anti-MUC5AC antibodies as a vehicle for therapeutic nuclides in treating PDAC [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Highly Selective Targeting of Pancreatic Cancer in the Liver with a Near-Infrared Anti-MUC5AC Probe in a PDOX Mouse Model: A Proof-of-Concept Study

Turner

Cox

Neel

et al. 2023

JPM

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Accurately identifying metastatic disease is critical to directing the appropriate treatment in pancreatic cancer. Mucin 5AC is overexpressed in pancreatic cancer but absent in normal pancreas tissue. The present proof-of-concept study demonstrates the efficacy of an anti-mucin 5AC antibody conjugated to an IR800 dye (MUC5AC-IR800) to preferentially label a liver metastasis of pancreatic cancer (Panc Met) in a unique patient-derived orthotopic xenograft (PDOX) model. In orthotopic models, the mean tumor to background ratio was 1.787 (SD ± 0.336), and immunohistochemistry confirmed the expression of MUC5AC within tumor cells. MUC5AC-IR800 provides distinct visualization of pancreatic cancer liver metastasis in a PDOX mouse model, demonstrating its potential utility in staging laparoscopy and fluorescence-guided surgery.

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Exploiting the MUC5AC Antigen for Noninvasive Identification of Pancreatic Cancer

Cited by 5 publications

References 31 publications

Interrogating the Theranostic Capacity of a MUC16-Targeted Antibody for Ovarian Cancer

Interrogating the Theranostic Capacity of a MUC16-Targeted Antibody for Ovarian Cancer

Clinical Significance and Levels of NLRP3, MUC5AC, and MUC5B in Asthma

Highly Selective Targeting of Pancreatic Cancer in the Liver with a Near-Infrared Anti-MUC5AC Probe in a PDOX Mouse Model: A Proof-of-Concept Study

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