m276-SL-PBD eradicates tumors and instigates long-lasting tumor-free survival in Merkel cell carcinoma preclinical models
Summary: Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma, and immune checkpoint inhibitors (ICIs) are the only approved therapy; nonetheless, resistance is notable and there is a critical need for novel effective therapies. Recently, CD276 was identified as a promising...
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| Language: | English |
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Elsevier
2025-05-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225006972 |
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| author | Mikaela D. Kunika Aarthi Kannan Graham J. Velasco Yang Feng Steven Seaman Bhaba K. Das Dillon Pham Nils Lambrecht Haibo Zhao Brad St. Croix Ling Gao |
| author_facet | Mikaela D. Kunika Aarthi Kannan Graham J. Velasco Yang Feng Steven Seaman Bhaba K. Das Dillon Pham Nils Lambrecht Haibo Zhao Brad St. Croix Ling Gao |
| author_sort | Mikaela D. Kunika |
| collection | DOAJ |
| description | Summary: Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma, and immune checkpoint inhibitors (ICIs) are the only approved therapy; nonetheless, resistance is notable and there is a critical need for novel effective therapies. Recently, CD276 was identified as a promising therapeutic target in human cancers. In preclinical studies, a modified CD276 antibody-drug conjugate (ADC) with pyrrolobenzodiazepine (m276-SL-PBD) elicited more potent anti-tumor effects than two CD276 ADCs currently in clinical trials. Here, we uncover notable CD276 expression in MCC patient tumors, and demonstrate m276-SL-PBD efficacy against MCC preclinical models. Complete eradication is observed in all xenografts bearing CD276 expression, with 82% achieving 180-day tumor-free survival after 4 or 5 weekly doses, and m276-SL-PBD remained efficacious against relapsed tumors. Of clinical relevance, m276-SL-PBD retains its potency in MCC-bearing humanized mice. Importantly, no detectable adverse effects were observed. Thus, m276-SL-PBD is a promising therapy for patients unsuitable or resistant to ICIs. |
| format | Article |
| id | doaj-art-b143e85567dc4dce82f54c13ed7e3f8e |
| institution | OA Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-b143e85567dc4dce82f54c13ed7e3f8e2025-08-20T01:55:59ZengElsevieriScience2589-00422025-05-0128511243610.1016/j.isci.2025.112436m276-SL-PBD eradicates tumors and instigates long-lasting tumor-free survival in Merkel cell carcinoma preclinical modelsMikaela D. Kunika0Aarthi Kannan1Graham J. Velasco2Yang Feng3Steven Seaman4Bhaba K. Das5Dillon Pham6Nils Lambrecht7Haibo Zhao8Brad St. Croix9Ling Gao10Southern California Institute for Research and Education, Long Beach, CA 90822, USASouthern California Institute for Research and Education, Long Beach, CA 90822, USA; Department of Dermatology, University of California-Irvine, Irvine, CA 92697, USAPathology Department, Tibor Rubin VA Medical Center, VA Long Beach Healthcare System, Long Beach, CA 90822, USATumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USATumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USASouthern California Institute for Research and Education, Long Beach, CA 90822, USASouthern California Institute for Research and Education, Long Beach, CA 90822, USAPathology Department, Tibor Rubin VA Medical Center, VA Long Beach Healthcare System, Long Beach, CA 90822, USASouthern California Institute for Research and Education, Long Beach, CA 90822, USATumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USASouthern California Institute for Research and Education, Long Beach, CA 90822, USA; Department of Dermatology, University of California-Irvine, Irvine, CA 92697, USA; Dermatology Section, Tibor Rubin VA Medical Center, VA Long Beach Healthcare System, Long Beach, CA 90822, USA; Corresponding authorSummary: Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma, and immune checkpoint inhibitors (ICIs) are the only approved therapy; nonetheless, resistance is notable and there is a critical need for novel effective therapies. Recently, CD276 was identified as a promising therapeutic target in human cancers. In preclinical studies, a modified CD276 antibody-drug conjugate (ADC) with pyrrolobenzodiazepine (m276-SL-PBD) elicited more potent anti-tumor effects than two CD276 ADCs currently in clinical trials. Here, we uncover notable CD276 expression in MCC patient tumors, and demonstrate m276-SL-PBD efficacy against MCC preclinical models. Complete eradication is observed in all xenografts bearing CD276 expression, with 82% achieving 180-day tumor-free survival after 4 or 5 weekly doses, and m276-SL-PBD remained efficacious against relapsed tumors. Of clinical relevance, m276-SL-PBD retains its potency in MCC-bearing humanized mice. Importantly, no detectable adverse effects were observed. Thus, m276-SL-PBD is a promising therapy for patients unsuitable or resistant to ICIs.http://www.sciencedirect.com/science/article/pii/S2589004225006972therapeutic procedurebiotechnologycancer |
| spellingShingle | Mikaela D. Kunika Aarthi Kannan Graham J. Velasco Yang Feng Steven Seaman Bhaba K. Das Dillon Pham Nils Lambrecht Haibo Zhao Brad St. Croix Ling Gao m276-SL-PBD eradicates tumors and instigates long-lasting tumor-free survival in Merkel cell carcinoma preclinical models iScience therapeutic procedure biotechnology cancer |
| title | m276-SL-PBD eradicates tumors and instigates long-lasting tumor-free survival in Merkel cell carcinoma preclinical models |
| title_full | m276-SL-PBD eradicates tumors and instigates long-lasting tumor-free survival in Merkel cell carcinoma preclinical models |
| title_fullStr | m276-SL-PBD eradicates tumors and instigates long-lasting tumor-free survival in Merkel cell carcinoma preclinical models |
| title_full_unstemmed | m276-SL-PBD eradicates tumors and instigates long-lasting tumor-free survival in Merkel cell carcinoma preclinical models |
| title_short | m276-SL-PBD eradicates tumors and instigates long-lasting tumor-free survival in Merkel cell carcinoma preclinical models |
| title_sort | m276 sl pbd eradicates tumors and instigates long lasting tumor free survival in merkel cell carcinoma preclinical models |
| topic | therapeutic procedure biotechnology cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225006972 |
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