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This study demonstrates that combining ADCs with immune-stimulating antibody conjugates (ISACs) improves efficacy versus either agent alone. Two non-competitive antibodies enhance tumor antigen internalization to deliver a toxic payload, while improved FcγR engagement enables STING agonist delivery to immune cells. Results show reduced tumor volume and tolerable side effects with limited weight loss.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/combining-antibody-conjugates-with-cytotoxic-and-immune-stimulating-payloads-maximizes-anti-cancer-activity/355664/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/combining-antibody-conjugates-with-cytotoxic-and-immune-stimulating-payloads-maximizes-anti-cancer-activity/355664.png","ImageObject",300,407,{"name":92,"@type":93},"Putri","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does combining ADCs with immune-stimulating conjugates address?","Question",{"text":112,"@type":113},"The approach targets limited durability and resistance in ADC therapy and the reduced benefit of checkpoint inhibitors in immunologically cold tumors with few tumor-infiltrating lymphocytes.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does the study’s design improve delivery to cancer cells and immune cells?",{"text":117,"@type":113},"Two non-competitive antibodies increase internalization of a tumor-associated antigen (CEA) to facilitate toxic payload entry, while enhanced FcγR engagement helps the ISAC deliver the STING agonist into immune cells.",{"name":119,"@type":110,"acceptedAnswer":120},"What treatment outcomes and safety observations are reported for the combination?",{"text":121,"@type":113},"After treatment, the combination group shows average tumor volume around ~40% of the ADC group and ~30% of the PBS group at day 14. Side effects are described as tolerable, with average weight loss of 7% or less after injections.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},355664,1790183663,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962085571259,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Combining antibody conjugates with cytotoxic and immune-stimulating payloads maximizes  \nanti-cancer activity  \nTiexin Wang 1,2 , Dong Jun Koo 1, Peter M. Tessier 1,2,3,4,5  and Greg M. Thurber 1,3,6   \n1 Department of Chemical Engineering, University of Michigan, Ann Arbor, USA  \n2 Biointerfaces Institute, University of Michigan, Ann Arbor, USA  \n3 Department of Biomedical Engineering, University of Michigan, Ann Arbor, USA  \n4 Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, USA  \n5 Program in Chemical Biology, University of Michigan, Ann Arbor, USA  \n6 Rogel Cancer Center, University of Michigan, Ann Arbor, USA  \nKeywords  \nADC; antibody–drug conjugate; CEA; immune-stimulating antibody conjugate; ISAC; STING agonist  \nCorrespondence  \nP. M. Tessier and G. M. Thurber, Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA  \nTel: +1 (734) 763-1486 and +1 (734)  \n764-8722  \nE-mail: [ptessier@umich.edu](ptessier@umich.edu); gthurber@ [umich.edu](umich.edu)  \n(Received 28 July 2025, revised 24 October 2025, accepted 17 December 2025, available online 6 January 2026)  \ndoi:10 . 1002/1878-0261 .70198  \nAntibody–drug conjugates (ADCs) are rapidly expanding in the clinical treatment of cancers, and combinations with checkpoint inhibitors further enhance antitumor activity in patients sensitive to such immunotherapy. However, a method to improve treatment durability, including cases where immunologically cold tumors limit checkpoint inhibitor activity, is needed. Here, we demonstrate that mixtures of ADCs and immune-stimulating antibody conjugates (ISACs) enhance efficacy compared to either agent alone. Our approach utilizes two non-competitive antibodies to increase the internalization of a tumor-associated antigen (carcinoembryonic antigen, CEA), facilitating the entry of the toxic payload (SN-38, a topoisomerase I inhibitor) into cancer cells. With improved FccR engagement, the designed ISAC better delivered the immunostimulatory agent (STING agonist) into immune cells. After treatment, the average tumor volume in the combination group was ~40% of the ADC group, and ~ 30% of the PBS group at day 14 . The side effects of combination therapy were tolerable, with an average weight loss of 7% or less after injections. We expect this approach can be readily extended to other ADCs to enhance their efficacy, including for the treatment of immunologically cold tumors.  \n1. Introduction  \nAntibody–drug conjugates (ADCs) are now well established as potent anti-cancer therapeutics due to their combination of specific targeting of tumor-associated antigens and intracellular delivery of toxic payloads. Blockbuster successes such as Kadcyla and Enhertu—both of which target HER2—highlight the great  \npotential of this class of therapeutics. However, direct cancer cell killing alone using ADCs is often not sufficient for durable responses due to the development of drug resistance [1] . Factors leading to drug resistance include insufficient tumor penetration, receptor downregulation, heterogeneous antigen expression, and loss  \nAbbreviations  \nADC, antibody–drug conjugates; ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CEA, carcinoembryonic antigen; DAR, drug-to-antibody ratio; HER2, human epidermal growth factor receptor 2; HI FBS, fetal bovine serum, heat inactivated; ISAC, immune-stimulating antibody conjugate; PBS, phosphate-buffered saline; STING, stimulators of interferon genes; TLR, toll-like receptor; Trop2, trophoblast cell surface antigen 2 .  \n1220 Molecular Oncology 20 (2026) 1220–1236 ª 2026 The Author(s) . Molecular Oncology published by John Wiley & Sons Ltd on behalf of  \nFederation of European Biochemical Societies.  \nThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nT. Wang et al","cbCaie7ToSeperFf","https://ap.wps.com/l/cbCaie7ToSeperFf","pdf",1615500,17,"English","# Introduction\n## ADCs and the need to overcome resistance\n## ADCs combined with checkpoint inhibitors\n## Cold tumors and innate immune activation via TLR/STING","[{\"question\":\"What problem does combining ADCs with immune-stimulating conjugates address?\",\"answer\":\"The approach targets limited durability and resistance in ADC therapy and the reduced benefit of checkpoint inhibitors in immunologically cold tumors with few tumor-infiltrating lymphocytes.\"},{\"question\":\"How does the study’s design improve delivery to cancer cells and immune cells?\",\"answer\":\"Two non-competitive antibodies increase internalization of a tumor-associated antigen (CEA) to facilitate toxic payload entry, while enhanced FcγR engagement helps the ISAC deliver the STING agonist into immune cells.\"},{\"question\":\"What treatment outcomes and safety observations are reported for the combination?\",\"answer\":\"After treatment, the combination group shows average tumor volume around ~40% of the ADC group and ~30% of the PBS group at day 14. Side effects are described as tolerable, with average weight loss of 7% or less after injections.\"}]","Combining antibody conjugates with cytotoxic and immune-stimulating payloads maximizes anti-cancer activity | PDF",1790120414,43]