{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T04:09:00Z","timestamp":1780546140088,"version":"3.54.1"},"reference-count":70,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:00:00Z","timestamp":1779494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GLF funding","award":["R01AI186995"],"award-info":[{"award-number":["R01AI186995"]}]},{"name":"NCI Cancer Center","award":["P30CA023108"],"award-info":[{"award-number":["P30CA023108"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cancer is a leading cause of death in dogs, and incidence rates in dogs exceed those in humans. Current therapeutic options for canine cancer patients remain limited, with most treatments focused on palliative care. Immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies that have transformed cancer therapy and expanded the therapeutic options in humans could offer the same clinical benefit in canine cancer patients. This study details the engineering and functional characterization of mouse and chimeric mouse\u2013canine anti-canine PD-1 (cPD-1) monoclonal antibodies. We demonstrate that anti-cPD-1 antibodies block the interaction between cPD-1 and its ligand cPD-L1, thereby inhibiting this immune signaling pathway. In a proof-of-concept study in seven companion canine cancer patients, intratumoral therapy with the lead anti-cPD-1 antibody (HugPetmab) was safe, well-tolerated, had no observed adverse events, and showed evidence of tumor control in a subset of injected tumors. These findings support the potential of HugPetmab antibody as an immunotherapeutic option for treating canine cancer patients.<\/jats:p>","DOI":"10.3390\/cells15110966","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T10:19:52Z","timestamp":1779877192000},"page":"966","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of Anti-Canine PD-1 Antibodies"],"prefix":"10.3390","volume":"15","author":[{"given":"Colin J.","family":"Hartman","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 621 Rubin Building\u2014HB7936, 1 Medical Center Drive, Lebanon, NH 03756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Sergent","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 621 Rubin Building\u2014HB7936, 1 Medical Center Drive, Lebanon, NH 03756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Barbara Emilia","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Clinic for Radiation Oncology and Medical Oncology, University Animal Hospital, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland"},{"name":"Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga R.","family":"Ch\u00e1vez-Alexander-Anderson","sequence":"additional","affiliation":[{"name":"Villareal Garza, Hospital Veterinario, Monterrey 64390, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis A.","family":"Perez Alonso","sequence":"additional","affiliation":[{"name":"Villareal Garza, Hospital Veterinario, Monterrey 64390, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Lines","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 621 Rubin Building\u2014HB7936, 1 Medical Center Drive, Lebanon, NH 03756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3018-466X","authenticated-orcid":false,"given":"Juan Carlos","family":"Pinto-C\u00e1rdenas","sequence":"additional","affiliation":[{"name":"DIAGSA, Diagn\u00f3stico de Salud Animal, Naucalpan 53910, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Luna D\u00e1valos","sequence":"additional","affiliation":[{"name":"VETCONNECT Diagn\u00f3stico por Imagen, Monterrey 64780, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2830-5650","authenticated-orcid":false,"given":"Anna M.","family":"Schmoker","sequence":"additional","affiliation":[{"name":"Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Palisoul","sequence":"additional","affiliation":[{"name":"Center for Clinical Genomics and Advanced Technology, Department of Pathology and Laboratory Medicine at Dartmouth Hitchcock Health, Lebanon, NH 03756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4086-1564","authenticated-orcid":false,"given":"Johannes","family":"vom Berg","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0975-4744","authenticated-orcid":false,"given":"Xiaoxuan","family":"Ge","sequence":"additional","affiliation":[{"name":"Thayer School of Engineering, Dartmouth College, Hanover, NH 03766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4697-8405","authenticated-orcid":false,"given":"Jay L.","family":"Rothstein","sequence":"additional","affiliation":[{"name":"Lifordi Immunotherapeutics, Lebanon, NH 03756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-3476","authenticated-orcid":false,"given":"Margaret E.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 621 Rubin Building\u2014HB7936, 1 Medical Center Drive, Lebanon, NH 03756, USA"},{"name":"Thayer School of Engineering, Dartmouth College, Hanover, NH 03766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0624-974X","authenticated-orcid":false,"given":"Steven","family":"Fiering","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 621 Rubin Building\u2014HB7936, 1 Medical Center Drive, Lebanon, NH 03756, USA"},{"name":"Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randolph J.","family":"Noelle","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 621 Rubin Building\u2014HB7936, 1 Medical Center Drive, Lebanon, NH 03756, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4941-1110","authenticated-orcid":false,"given":"Hugo","family":"Arias-Pulido","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 621 Rubin Building\u2014HB7936, 1 Medical Center Drive, Lebanon, NH 03756, USA"},{"name":"Canine Cancer Alliance, Bellevue, WA 98005, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20140231","DOI":"10.1098\/rstb.2014.0231","article-title":"Comparative oncology: What dogs and other species can teach us about humans with cancer","volume":"370","author":"Schiffman","year":"2015","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_2","unstructured":"AVMA (2025, April 05). Cancer in Pets. Available online: https:\/\/www.avma.org\/resources\/pet-owners\/petcare\/cancer-pets."},{"key":"ref_3","unstructured":"NIH, and NCfCR (2025, April 05). Comparative Oncology Program, Available online: https:\/\/ccr.cancer.gov\/comparative-oncology-program\/about."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1939-1676.2011.0695.x","article-title":"Mortality in north american dogs from 1984 to 2004: An investigation into age-, size-, and breed-related causes of death","volume":"25","author":"Fleming","year":"2011","journal-title":"J. Vet. Intern. Med."},{"key":"ref_5","first-page":"17","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1001\/jamainternmed.2022.2476","article-title":"Leading Causes of Death in the US During the COVID-19 Pandemic, March 2020 to October 2021","volume":"182","author":"Shiels","year":"2022","journal-title":"JAMA Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e12737","DOI":"10.1111\/acel.12737","article-title":"The companion dog as a model for human aging and mortality","volume":"17","author":"Hoffman","year":"2018","journal-title":"Aging Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.cell.2015.03.030","article-title":"Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential","volume":"161","author":"Sharma","year":"2015","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrc.2016.36","article-title":"Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy","volume":"16","author":"Topalian","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-pathol-042020-042741","article-title":"Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance","volume":"16","author":"Bagchi","year":"2021","journal-title":"Annu. Rev. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1200\/JCO.21.02229","article-title":"Long-Term Outcomes with Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients with Advanced Melanoma","volume":"40","author":"Wolchok","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1038\/ni.2762","article-title":"A rheostat for immune responses: The unique properties of PD-1 and their advantages for clinical application","volume":"14","author":"Okazaki","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1146\/annurev-immunol-032414-112049","article-title":"Coinhibitory Pathways in Immunotherapy for Cancer","volume":"34","author":"Baumeister","year":"2016","journal-title":"Annu. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1093\/intimm\/8.5.765","article-title":"Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes","volume":"8","author":"Agata","year":"1996","journal-title":"Int. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.it.2013.07.003","article-title":"B7 family checkpoint regulators in immune regulation and disease","volume":"34","author":"Ceeraz","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1084\/jem.192.7.1027","article-title":"Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation","volume":"192","author":"Freeman","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Klingemann, H. (2021). Immunotherapy for Dogs: Still Running Behind Humans. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.665784"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Dow, S. (2020). A Role for Dogs in Advancing Cancer Immunotherapy Research. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02935"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1111\/vco.12294","article-title":"PD-1 expression by canine T cells and functional effects of PD-1 blockade","volume":"15","author":"Coy","year":"2017","journal-title":"Vet. Comp. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8951","DOI":"10.1038\/s41598-017-09444-2","article-title":"A canine chimeric monoclonal antibody targeting PD-L1 and its clinical efficacy in canine oral malignant melanoma or undifferentiated sarcoma","volume":"7","author":"Maekawa","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.vetimm.2018.02.007","article-title":"Development and characterization of monoclonal antibodies against canine PD-1 and PD-L1","volume":"198","author":"Nemoto","year":"2018","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"18311","DOI":"10.1038\/s41598-020-75533-4","article-title":"A pilot clinical study of the therapeutic antibody against canine PD-1 for advanced spontaneous cancers in dogs","volume":"10","author":"Igase","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Choi, J.W., Withers, S.S., Chang, H., Spanier, J.A., De La Trinidad, V.L., Panesar, H., Fife, B.T., Sciammas, R., Sparger, E.E., and Moore, P.F. (2020). Development of canine PD-1\/PD-L1 specific monoclonal antibodies and amplification of canine T cell function. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0235518"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Minoli, L., Licenziato, L., Kocikowski, M., Cino, M., Dziubek, K., Iussich, S., Fanelli, A., Morello, E., Martano, M., and Hupp, T. (2022). Development of Monoclonal Antibodies Targeting Canine PD-L1 and PD-1 and Their Clinical Relevance in Canine Apocrine Gland Anal Sac Adenocarcinoma. Cancers, 14.","DOI":"10.3390\/cancers14246188"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1158\/2767-9764.CRC-22-0468","article-title":"Development of an Anti-canine PD-L1 Antibody and Caninized PD-L1 Mouse Model as Translational Research Tools for the Study of Immunotherapy in Humans","volume":"3","author":"Oh","year":"2023","journal-title":"Cancer Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2287250","DOI":"10.1080\/19420862.2023.2287250","article-title":"Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors","volume":"15","author":"Yoshimoto","year":"2023","journal-title":"mAbs"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kocikowski, M., Dziubek, K., W\u0119grzyn, K., Hrabal, V., Zavadil-Kokas, F., Vojtesek, B., Alfaro, J.A., Hupp, T., and Parys, M. (2024). Comparative characterization of two monoclonal antibodies targeting canine PD-1. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1382576"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"201036","DOI":"10.1016\/j.omton.2025.201036","article-title":"Nanobody-based canine PD-L1-targeting immune checkpoint inhibitors for cancer therapy in dogs","volume":"33","author":"Subran","year":"2025","journal-title":"Mol. Ther. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2004638","DOI":"10.1080\/19420862.2021.2004638","article-title":"Development of a fully canine anti-canine CTLA4 monoclonal antibody for comparative translational research in dogs with spontaneous tumors","volume":"13","author":"Mason","year":"2021","journal-title":"mAbs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"20763","DOI":"10.1038\/s41598-021-00325-3","article-title":"Nanobody-based CTLA4 inhibitors for immune checkpoint blockade therapy of canine cancer patients","volume":"11","author":"Marable","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Maekawa, N., Konnai, S., Watari, K., Takeuchi, H., Nakanishi, T., Tachibana, T., Hosoya, K., Kim, S., Kinoshita, R., and Owaki, R. (2025). Development of caninized anti-CTLA-4 antibody as salvage combination therapy for anti-PD-L1 refractory tumors in dogs. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1570717"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Sergent, P., Pinto-C\u00e1rdenas, J.C., Carrillo, A.J.A., D\u00e1valos, D.L., P\u00e9rez, M.D.G., Lechuga, D.A.M., Alonso-Miguel, D., Schaafsma, E., Cuarenta, A.J., and Mu\u00f1oz, D.C. (2024). An Abscopal Effect on Lung Metastases in Canine Mammary Cancer Patients Induced by Neoadjuvant Intratumoral Immunotherapy with Cowpea Mosaic Virus Nanoparticles and Anti-Canine PD-1. Cells, 13.","DOI":"10.3390\/cells13171478"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/s41596-018-0082-x","article-title":"Single-pot, solid-phase-enhanced sample preparation for proteomics experiments","volume":"14","author":"Hughes","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/pmic.201200439","article-title":"Comet: An open-source MS\/MS sequence database search tool","volume":"13","author":"Eng","year":"2013","journal-title":"Proteomics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature10098","article-title":"Global quantification of mammalian gene expression control","volume":"473","author":"Busse","year":"2011","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zimmermann, A.B.E., Taskoparan, B., Fuchs, D., Pantelyushin, S., Maheswaran, M., Schnyder, M., Hartnack, S., Bley, C.R., and Berg, J.V. (2025). Prior corticosteroid treatment alters cPBMC composition and IFN\u03b3 response to immunotherapy in canine cancer. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1544949"},{"key":"ref_37","unstructured":"Kiupel, M. (2019). Classification of canine mammary tumors. Surgical Pathology of Tumors of Domestic Animals, Davis-Thompson DVM Foundation. Volume 2: Mammary Tumors."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1177\/0300985812447830","article-title":"Prognostic value of histological grading in noninflammatory canine mammary carcinomas in a prospective study with two-year follow-up: Relationship with clinical and histological characteristics","volume":"50","author":"Clemente","year":"2013","journal-title":"Vet. Pathol."},{"key":"ref_39","unstructured":"Withrow, S.J., and MacEwen, E.G. (2001). Tumors of the mammary gland. Small Animal Clinical Oncology, W.B. Saunders. [3rd ed.]."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1177\/0300985814521638","article-title":"Histologic grading of canine mast cell tumor: Is 2 better than 3?","volume":"52","author":"Sabattini","year":"2015","journal-title":"Vet. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1177\/0300985817747325","article-title":"Assessment of Canine Mast Cell Tumor Mortality Risk Based on Clinical, Histologic, Immunohistochemical, and Molecular Features","volume":"55","author":"Horta","year":"2018","journal-title":"Vet. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1177\/030098588402100503","article-title":"Canine cutaneous mast cell tumor: Morphologic grading and survival time in 83 dogs","volume":"21","author":"Patnaik","year":"1984","journal-title":"Vet. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/j.1476-5829.2010.00244.x","article-title":"Development of a questionnaire assessing health-related quality-of-life in dogs and cats with cancer","volume":"9","author":"Lynch","year":"2011","journal-title":"Vet. Comp. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/vco.12677","article-title":"Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats","volume":"19","author":"LeBlanc","year":"2021","journal-title":"Vet. Comp. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1073\/pnas.0712278105","article-title":"The PD-1\/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors","volume":"105","author":"Lin","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/j.celrep.2017.07.027","article-title":"Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells","volume":"20","author":"Okada","year":"2017","journal-title":"Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1158\/0008-5472.CAN-19-3133","article-title":"Targeting Glycosylated PD-1 Induces Potent Antitumor Immunity","volume":"80","author":"Sun","year":"2020","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"17252","DOI":"10.1038\/s41598-019-53463-0","article-title":"Phosphorylation of PD-1-Y248 is a marker of PD-1-mediated inhibitory function in human T cells","volume":"9","author":"Bardhan","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.vetimm.2013.10.018","article-title":"Comparative functional characterization of canine IgG subclasses","volume":"157","author":"Bergeron","year":"2014","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"D1262","DOI":"10.1093\/nar\/gkab1136","article-title":"IMGT\u00ae databases, related tools and web resources through three main axes of research and development","volume":"50","author":"Manso","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10302","DOI":"10.1021\/ja203638y","article-title":"Mechanism of immunoglobulin G4 Fab-arm exchange","volume":"133","author":"Rispens","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.molimm.2012.06.012","article-title":"Fc-Fc interactions of human IgG4 require dissociation of heavy chains and are formed predominantly by the intra-chain hinge isomer","volume":"53","author":"Rispens","year":"2013","journal-title":"Mol. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1007\/s10529-007-9449-8","article-title":"Characterization of lower molecular weight artifact bands of recombinant monoclonal IgG1 antibodies on non-reducing SDS-PAGE","volume":"29","author":"Liu","year":"2007","journal-title":"Biotechnol. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1126\/science.aar4060","article-title":"Cancer immunotherapy using checkpoint blockade","volume":"359","author":"Ribas","year":"2018","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/s41392-023-01522-4","article-title":"Immune checkpoint therapy for solid tumours: Clinical dilemmas and future trends","volume":"8","author":"Sun","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41523-023-00508-3","article-title":"Immunotherapy in breast cancer: An overview of current strategies and perspectives","volume":"9","author":"Debien","year":"2023","journal-title":"npj Breast Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1097\/CCO.0000000000000878","article-title":"Immunotherapy and breast cancer: An overview","volume":"34","author":"Mezni","year":"2022","journal-title":"Curr. Opin. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1056\/NEJMoa2201445","article-title":"PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer","volume":"386","author":"Cercek","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1158\/1078-0432.CCR-24-0861","article-title":"Tumor-Localized Interleukin-2 and Interleukin-12 Combine with Radiation Therapy to Safely Potentiate Regression of Advanced Malignant Melanoma in Pet Dogs","volume":"30","author":"Stinson","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1158\/1078-0432.CCR-23-0006","article-title":"Collagen-Anchored Interleukin-2 and Interleukin-12 Safely Reprogram the Tumor Microenvironment in Canine Soft-Tissue Sarcomas","volume":"29","author":"Stinson","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Boss, M.-K., Watts, R., Harrison, L.G., Hopkins, S., Chow, L., Trageser, E., Easton, C., LaRue, S.M., Regan, D., and Dewhirst, M.W. (2022). Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40\/TLR Agonist Immunotherapy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020826"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1158\/1535-7163.MCT-24-0317","article-title":"Preclinical Evaluation of an Anchored Immunotherapy Strategy with Aluminum Hydroxide-Tethered IL-12 in Dogs with Advanced Malignant Melanoma","volume":"24","author":"Barbosa","year":"2025","journal-title":"Mol. Cancer Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1111\/vco.12829","article-title":"Long-term survival of dogs with stage 4 oral malignant melanoma treated with anti-canine PD-1 therapeutic antibody: A follow-up case report","volume":"20","author":"Igase","year":"2022","journal-title":"Vet. Comp. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.4142\/jvs.23144","article-title":"Proof-of-concept study of the caninized anti-canine programmed death 1 antibody in dogs with advanced non-oral malignant melanoma solid tumors","volume":"25","author":"Igase","year":"2024","journal-title":"J. Vet. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Xu, S., Xie, J., Wang, S., Tang, N., Feng, J., Su, Y., and Li, G. (2023). Reversing stage III oral adenocarcinoma in a dog treated with anti-canine PD-1 therapeutic antibody: A case report. Front. Vet. Sci., 10.","DOI":"10.3389\/fvets.2023.1144869"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10549-021-06480-5","article-title":"Immunotherapy toxicity: Identification and management","volume":"192","author":"Gumusay","year":"2022","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.1200\/JCO.2015.64.8931","article-title":"Pembrolizumab in Patients with Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study","volume":"34","author":"Nanda","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e207911","DOI":"10.1001\/jamanetworkopen.2020.7911","article-title":"Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients with Cancer","volume":"3","author":"Sheth","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejca.2022.05.024","article-title":"Feasibility, safety and efficacy of human intra-tumoral immuno-therapy. Gustave Roussy\u2019s initial experience with its first 100 patients","volume":"172","author":"Tselikas","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s40425-019-0586-0","article-title":"Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics","volume":"7","author":"Davda","year":"2019","journal-title":"J. Immunother. 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