[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-376360-105":59,"doc-detail-376360-en":122},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":115,"head_meta":117,"extra_data":119,"updated_unix":121},105,"en","development-of-a-prame-pmhc-targeted-t-cell-engager-for-solid-tumor-therapy-report","Development of a PRAME pMHC targeted T cell engager for solid tumor therapy - Report","","Bispecific T cell engager (TCE) therapies have shown major clinical success for hematological cancers, but limited antigen selectivity restricts progress in solid tumors. To reduce on-target, off-tumor toxicity caused by low tumor-associated antigen expression in healthy tissues, this work characterizes PRAME as a highly tumor-selective antigen. A PRAME425–433 proteasomal peptide presented on MHC I is identified as an effective TCE target. A TCR-mimic antibody screening cascade prioritizes functional specificity in off-target cytotoxicity assays, leading to TCR-like binders. Cryo-EM confirms an anti-PRAME425 pMHC TCR-mimic structure and demonstrates PRAME425 pMHC-specific tumor killing, supporting a new class of anti-PRAME pMHC biologics.",{"@graph":69,"@context":114},[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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/development-of-a-prame-pmhc-targeted-t-cell-engager-for-solid-tumor-therapy-report/376360/",{"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/development-of-a-prame-pmhc-targeted-t-cell-engager-for-solid-tumor-therapy-report/376360.png","ImageObject",300,407,{"name":92,"@type":93},"Well Done","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-27","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108],{"name":109,"@type":110,"acceptedAnswer":111},"How did the study evaluate antibody specificity beyond standard pMHC binding assays?","Question",{"text":112,"@type":113},"It used a TCR-mimic antibody screening cascade that prioritizes screening anti-PRAME pMHC binders in off-target T cell dependent cellular cytotoxicity assays. This approach aims to detect overrecognition of off-target peptides and reduce unwanted MHCI-related activity.","Answer","https://schema.org",{"og:url":83,"og:type":116,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":118,"canonical":83},"index,follow",{"doc_id":120,"site_id":62},376360,1790246963,{"code":4,"msg":5,"data":123},{"doc_id":120,"user_id":124,"nickname":92,"user_avatar":125,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":126,"file_id":127,"file_url":128,"file_type":129,"file_size":130,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":131,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":132,"faqs":133,"seo_title":134,"seo_description":67,"update_tm":135,"read_time":136},5909892210082,"https://ap-avatar.wpscdn.com/avatar/56001069da27c9f41e8?x-image-process=image/resize,m_fixed,w_180,h_180&k=1789614185077863061","MABS  \n2025, VOL. 17, NO. 1, 2563773 [https://doi.org/10.1080/19420862.2025.2563773](https://doi.org/10.1080/19420862.2025.2563773)  \nREPORT  \nDevelopment of a PRAME pMHC targeted T cell engager for solid tumor therapy  \nKatarzyna Skrzypczynskaa,*, Kristin Schimertb, Heather Stephensonc, In Kyoung Mahd, David Mortensone, Kelli Boydd, Timothy Hardmana,f, Nikolai Novikovc, Elbert Setoc, Sabrina Luc, Randy Yenc, Brian Leec, Min Wangg, Don Kangg, Ying Huangg, Xinchao Yue, Magdeleine Hungc, Sheng Dingc, Nathan Thomsenc, and Nicole Schirle Oakdale c  \naOncology, Gilead Sciences, Inc, Foster City, CA, USA; bDiscovery Sciences and Technology, Gilead Sciences, Inc., Foster City, CA, USA; cProtein Therapeutics, Gilead Sciences, Inc., Foster City, CA, USA; dNonclinical Safety and Pathobiology, Gilead Sciences, Inc., Foster City, CA, USA; eStructural Biology and Chemistry, Gilead Sciences, Inc., Foster City, CA, USA; fUCLA Anderson School of Management, Los Angeles, CA, USA; gResearch Data Science, Gilead Sciences, Inc., Foster City, CA, USA  \nABSTRACT  \nBispecific T cell engager (TCE) therapies have demonstrated transformative clinical success in the treatment of hematological cancers, but the lack of antigens that are sufficiently selective for malignant cells has hampered the success of TCEs in the solidtumor space. To overcome the on-target, off-tumor toxicities that result from the expression of even low levels of tumor-associated antigens in healthy tissues, we sought to identify a TCE target with highly tumor-restricted expression patterns. Here, we characterize cancer-testes antigen Preferentially Expressed Antigen in Melanoma (PRAME) as a highly selective tumor antigen and identify a proteasomal degradation peptide PRAME425–433 (PRAME425) presented in the context of major histocompatibility complex I (MHCI) as an attractive TCE target. We designed a TCR-mimic (TCRm) antibody screening cascade that prioritizes screening anti-PRAME pMHC binders in off-target T cell dependent cellular cytotoxicity assays in a potent TCE format, rather than relying solely on traditional pMHC binding assays, to determine specificity. Using this screening cascade, we discovered antibodies that selectively bind PRAME425 pMHC without overrecognition of off-target peptides or MHCI via a TCR-like binding geometry. We further solved the first structure of an anti-PRAME425 pMHC TCRm antibody in complex with PRAME425/HLA-A *02:01 using cryo electron microscopy to confirm the TCRm antibody binds in a TCR-like binding geometry and specifically recognizes the PRAME425 peptide. By formatting these novel TCRm antibodies into potent TCEs, we demonstrate PRAME425 pMHC-specific killing of tumor cells, representing a new class of anti-PRAME pMHC biologics.  \nARTICLE HISTORY  \nReceived 17 July 2025 Revised 9 September 2025 Accepted 15 September 2025  \nKEYWORDS  \nPRAME; TCR-mimic (TCRm) antibody; T cell engager; solid tumor; Cancer testes antigen; pMHC complex; immunotherapy; diabody  \nIntroduction  \nT cell engagers (TCEs) are bispecific antibodies that induce T cell-mediated tumor cell killing through simultaneous engagement of a tumor antigen on cancer cells and the CD3 subunit of the T cell receptor (TCR) on T cells. TCEs for the treatment ofhematological cancers have shown immense clinical benefit and complete responses, demonstrating the transformative promise of this therapeutic modality.1 By definition, the abundance of solid tumor-associated antigens (TAAs), such as EpCAM, EGFR, CEA, or HER2, is increased in malignant cells compared with healthy tissues. However, TAA expression in normal cells is often present at levels sufficient to result in cytotoxicity in healthy tissues. On-target, off-tumor toxicity has long been an obstacle hindering the development of TCEs that offer the same deep and durable antitumor responses in solid tumors as those attained against hematological malignancies.2 In response to these  \nCONTACT Nicole Schirle Oakdale  [nicole.schirleoak","cbCaijDCF7xxawEs","https://ap.wps.com/l/cbCaijDCF7xxawEs","pdf",3323844,"English","# Abstract\n# Introduction\n## TCEs and the challenge of on-target, off-tumor toxicity\n## Cancer-testis antigens and PRAME as target candidates","[{\"question\":\"How did the study evaluate antibody specificity beyond standard pMHC binding assays?\",\"answer\":\"It used a TCR-mimic antibody screening cascade that prioritizes screening anti-PRAME pMHC binders in off-target T cell dependent cellular cytotoxicity assays. This approach aims to detect overrecognition of off-target peptides and reduce unwanted MHCI-related activity.\"}]","Development of a PRAME pMHC targeted T cell engager for solid tumor therapy - Report | PDF",1790218363,48]