[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-331824-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-331824-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","tumor-resistance-to-anti-mesothelin-car-t-cells-caused-by-binding-to-shed-mesothelin-is-overcome-by-targeting-ajuxtamembrane-epitope","Tumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting ajuxtamembrane epitope","","Humanized anti-mesothelin CAR-T cells (h15B6) are developed to overcome tumor resistance driven by shed mesothelin. The study addresses a limitation of earlier anti-MSLN antibodies that bind shed MSLN, which can block productive engagement with tumor cells. h15B6 binds next to the membrane at a protease-sensitive region, avoids binding to shed MSLN, and produces markedly higher anti-tumor activity than CAR-T targeting shed epitopes (e.g., SS1). In pancreatic cancer models, h15B6 CAR-T cells replicate in tumors/ascites and replace cancer cells, with no CAR-T found in SS1-treated tumors.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/tumor-resistance-to-anti-mesothelin-car-t-cells-caused-by-binding-to-shed-mesothelin-is-overcome-by-targeting-ajuxtamembrane-epitope/331824/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/tumor-resistance-to-anti-mesothelin-car-t-cells-caused-by-binding-to-shed-mesothelin-is-overcome-by-targeting-ajuxtamembrane-epitope/331824.png","ImageObject",300,407,{"name":42,"@type":43},"Logic","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-23","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",6,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why do anti-mesothelin CAR-T therapies face resistance in solid tumors?","Question",{"text":63,"@type":64},"The document explains that mesothelin is shed by proteases, and shed MSLN can bind and inactivate antibody-based therapies before they reach tumor cells. This can also prevent CAR-T cells from effectively engaging targets.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does the h15B6 CAR-T overcome the shed MSLN limitation?",{"text":68,"@type":64},"h15B6 binds near the membrane at the protease-sensitive region and does not bind shed MSLN. As a result, the CAR-T cells maintain strong anti-tumor activity compared with CAR-T that target shed epitopes.",{"name":70,"@type":61,"acceptedAnswer":71},"What experimental evidence supports the mechanism behind h15B6’s high activity?",{"text":72,"@type":64},"Using an OVCAR-8 intraperitoneal model, the study shows poorly active SS1-CAR-T cells are bound to shed MSLN, while highly active h15B6 CAR-T cells do not contain bound MSLN and can bind to and kill cancer cells.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},331824,1790013097,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,105,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":102,"show_sort_weight":103,"slug":104},"Technology",50,"technology",{"id":106,"doc_module":4,"doc_module_name":25,"category_name":107,"show_sort_weight":108,"slug":109},7,"Healthcare",40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":112,"slug":113},8,30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":111,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":115,"language":139,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":12,"update_tm":143,"read_time":144,"preview_page_count":4},1099513958762,"https://ap-avatar.wpscdn.com/avatar/1000023916a998db790?x-image-process=image/resize,m_fixed,w_180,h_180&k=1784791008015729253","RESEARCH ARTICLE  \nIMMUNOLOGY AND INFLAMMATION  \nTumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting ajuxtamembrane epitope  \nX. F. Liua, M. Ondaa, J. Schlomerb, L. Basselb , S. Kozlovb, C.-H. Taia, Q. Zhoua, W. Liua , H.-E. Tsaoa, R. Hassanc, M. Hoa , and I. Pastana,1 Contributed by I. Pastan; received October 6, 2023; accepted November 27, 2023; reviewed by Stephen Gottschalk and Michael G. Rosenblum  \nDespite many clinical trials, CAR-T cells are not yet approved for human solid tumor therapy. One popular target is mesothelin (MSLN) which is highly expressed on the surface of about 30% of cancers including mesothelioma and cancers ofthe ovary, pancreas, and lung. MSLN is shed by proteases that cleave near the C terminus, leaving a short peptide attached to the cell. Most anti-MSLN antibodies bind to shed MSLN, which can prevent their binding to target cells. To overcome this limitation, we developed an antibody (15B6) that binds next to the membrane at the protease-sensitive region, does not bind to shed MSLN, and makes CAR-T cells that have much higher anti-tumor activity than a CAR-T that binds to shed MSLN. We have now humanized the Fv (h15B6), so the CAR-T can be used to treat patients and showthat h15B6 CAR-T produces complete regressions in a hard-to-treat pancreatic cancer patient derived xenograft model, whereas CAR-T targeting a shed epitope (SS1) have no anti-tumor activity. In these pancreatic cancers, the h15B6 CAR-T replicates and replaces the cancer cells, whereas there are no CAR-T cells in the tumors receiving SS1 CAR-T. To determine the mechanism accounting for high activity, we used an OVCAR-8 intraperitoneal model to show that poorly active SS1-CAR-T cells are bound to shed MSLN, whereas highly active h15B6 CAR-T do not contain bound MSLN enabling them to bind to and kill cancer cells.  \nimmunotherapy | cancer | antibody | pancreatic cancer | ovarian cancer  \nCAR-T therapy has shown remarkable success in treating B cell malignancies and multiple myeloma (1–4). However, the development of CAR-T therapy for solid tumors has been less successful, and no CAR-T cells for solid tumors have been Food and Drug Administration (FDA) approved (4, 5). Mesothelin (MSLN) is a glycoprotein which is highly expressed on the surface of many types of cancers, including mesothelioma, and cancers of the ovary, pancreas, lung, and stomach, but not expressed on essential organs (6, 7) . This pattern of expression makes MSLN a very popular target for CAR-T and other antibody-based cancer therapies (8–11) . MSLN is shed from tumor cells and is found inside tumors and in ascites, where the levels are very high (12–14). Shed MSLN in the blood is a potential biomarker for cancer detection (15, 16). Shed MSLN, particularly inside tumors and in ascites, should be able to inactivate many anti-MSLN therapies before the agents reach the target cell. These include whole antibodies, antibody-drug conjugates, bispecific antibodies, and CAR-T cells. Thus, shed MSLN appears to be a major impediment to the success of antibody-based therapies. We recently described an anti-MSLN antibody, 15B6, that binds to MSLN at the cell membrane (Fig. 1A) and does not bind to shed MSLN (Fig. 1B),(17). The Fv of Mab 15B6 makes very active CAR-T cells that kill MSLN expressing tumor cells and produce complete regressions in solid tumor models (17). We compared its activity with CAR-T cells made with the SS1 Fv that binds at the amino terminus of shed MSLN and cell-bound MSLN (Fig. 1B) . We observe that the SS1 CAR-T have very low anti-tumor activity in mice and attribute the low activity to shed MSLN binding to and inactivating SS1 CAR-T cells (17) . We have now humanized the mouse Fv and shown that CAR-T cells made with the humanized Fv (h15B6 Fv) are as effective in cell killing and inducing complete tumor regressions. Using these humanized CAR-T cells, we directly demonstrate that they replicate ins","cbCaiimI0QN7vhja","https://ap.wps.com/l/cbCaiimI0QN7vhja","pdf",5368228,"English","# Background\n# Humanized CAR-T approach\n# Results\n## Humanized CAR-T construction\n# Significance","[{\"question\":\"Why do anti-mesothelin CAR-T therapies face resistance in solid tumors?\",\"answer\":\"The document explains that mesothelin is shed by proteases, and shed MSLN can bind and inactivate antibody-based therapies before they reach tumor cells. This can also prevent CAR-T cells from effectively engaging targets.\"},{\"question\":\"How does the h15B6 CAR-T overcome the shed MSLN limitation?\",\"answer\":\"h15B6 binds near the membrane at the protease-sensitive region and does not bind shed MSLN. As a result, the CAR-T cells maintain strong anti-tumor activity compared with CAR-T that target shed epitopes.\"},{\"question\":\"What experimental evidence supports the mechanism behind h15B6’s high activity?\",\"answer\":\"Using an OVCAR-8 intraperitoneal model, the study shows poorly active SS1-CAR-T cells are bound to shed MSLN, while highly active h15B6 CAR-T cells do not contain bound MSLN and can bind to and kill cancer cells.\"}]","Tumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting ajuxtamembrane epitope | PDF",1789995349,23]