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It recognizes a HER2 epitope distinct from trastuzumab and pertuzumab, redirecting T cells to kill HER2-low tumors including breast, gastric, and gastroesophageal junction adenocarcinoma. In vitro, TPP-45142 drives potent T cell–dependent cytotoxicity against HER2-low cancer cell lines, while in vivo it inhibits tumor growth in HER2-low breast cancer xenografts. The molecule shows high selectivity for tumor cells with low HER2 expression over normal cardiac cells and demonstrates a favorable cytokine release assay therapeutic index, supporting improved safety and potential next-generation TCE utility for challenging HER2-low cancers.",{"@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/tpp-45142-an-anti-her2-t-cell-engager-designed-for-selective-her2-low-cancer-immunotherapy/356585/",{"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/tpp-45142-an-anti-her2-t-cell-engager-designed-for-selective-her2-low-cancer-immunotherapy/356585.png","ImageObject",300,407,{"name":92,"@type":93},"Connor ","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-23",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 is TPP-45142 and what does it target?","Question",{"text":112,"@type":113},"TPP-45142 is a NANOBODY-based HER2-targeting TCE built on a T-cell receptor αβ framework. It binds a HER2 epitope distinct from trastuzumab and pertuzumab and redirects T cells to kill HER2-low cancers.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does TPP-45142 perform in preclinical settings?",{"text":117,"@type":113},"TPP-45142 mediates potent T cell–dependent cytotoxicity against HER2-low cancer cell lines in vitro. It also inhibits in vivo tumor growth of HER2-low breast cancer xenografts.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is selectivity and safety important for TCEs like TPP-45142?",{"text":121,"@type":113},"Solid-tumor targeting can produce on-target, off-tumor adverse effects when antigens are also present in healthy organs. TPP-45142 shows high selectivity for low-HER2 tumor cells versus normal cardiac cells and demonstrates a favorable therapeutic index based on a cytokine release assay.","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},356585,1790467218,{"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},687207022233,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","FIRST DISCLOSURE  \nTPP-45142—an Anti-HER2 T-cell Engager—Designed for Selective HER2-Low Cancer Immunotherapy  \nEvelyn De Tavernier1, Peter S. Kim2, Eduardo M. Bruch3, Virna F. Cortez-Retamozo4, Lien Timmerman1, Alyssa L. Flynn2, Wouter Van Overbeke1, Fabrice Tirode5, Valeria Cintra Barbosa-Lorenzi6,  \nPeter Piepenhagen6, Thuvan Dinh-Le7, Ernesto Luna7, Aiqun Li8, Ann Baker9, Alexey Rak10, Lily I. Pao2, and Ana Paula B. Vintm1  \n|  |  | A |  | B | S |  | T | R |  | A |  | C | T |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| 􀀶\u003Cbr>The standard of care for patients with HER2-positive cancers is well established, but a significant unmet need exists for patients with HER2-low tumors, who do not meet the eligibility criteria fortrastuzumab, and for patients with HER2-positive tumors, who are refractory to trastuzumab treatment. Therefore, in this study, we developed a NANOBODY domain–based HER2-targeting, T-cell receptor αβ–based T-cell engager (TCE) molecule—TPP-45142; it recognizes a HER2 epitope distinct from that recognized by trastuzumab and pertuzumab and redirects T cells to kill HER2-low cancers such as breast, gastric, and gastroesophageal junction adenocarcinoma cancers. TPP-45142 mediated potent T cell–dependent cytotoxicity against HER2-low cancer cell lines in vitro and inhibited in vivo tumor growth of HER2-low breast cancer xenografts. TPP-45142 was highly selective toward tumor cells expressing low HER2 levels than toward normal cardiac cells and exhibited a favorable therapeutic index as per a cytokine release\u003Cbr>assay. Thus, TPP-45142, with an improved safety profile, is a promising next-generation TCE for treating challenging HER2-low cancers.\u003Cbr>\u003Cbr>Introduction\u003Cbr>Advancements in immunotherapy have significantly transformed the clinical landscape of cancer treatment, with considerable attention on bispecific antibodies that redirect T cell–mediated cytotoxicity (1, 2) . The first-generation bispecific T cell–redirecting antibody, blinatumomab, has demonstrated remarkable clinical efficacy and is approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (3), establishing a precedent for the clinical advancement of cluster of differentiation (CD)3-based bispecific antibodies. Recently, numerous bispecific T-cell engagers (TCE) have been developed that target B-cell maturation antigen or G protein–coupled receptor family C group\u003Cbr>1NANOBODY Research Platform, Sanofi, Ghent, Belgium. 2Oncology Research, Sanofi, Cambridge, Massachusetts. 3Structural Biology, Sanofi, Cambridge, Massachusetts. 4In vivo Pharmacology, Sanofi, Cambridge, Massachusetts. 5Nuclear Imaging, Sanofi, Vitry-Sur-Seine, France. 6Global Discovery Pathology and Multimodal Imaging, Sanofi, Cambridge, Massachusetts. 7Vaccine Research and Development, Sanofi, Orlando, Florida. 8DMPK, Sanofi, Cambridge, Massachusetts. 9Preclinical Safety, Sanofi, Cambridge, Massachusetts. 10Integrated Drug Discovery, Sanofi, Vitry-Sur-Seine, France.\u003Cbr>E. De Tavernier and P. S. Kim contributed equally to this article.\u003Cbr>Corresponding Author: Ana Paula B. Vintm, Sanofi, Technologiepark 21, Gent\u003Cbr>9052, [Belgium. E-mai","cbCaifcAYJqoPMRx","https://ap.wps.com/l/cbCaifcAYJqoPMRx","pdf",13630394,15,"English","# Introduction\n## Solid-tumor challenges for T-cell redirection\n## HER2 as a target for immunotherapy","[{\"question\":\"What is TPP-45142 and what does it target?\",\"answer\":\"TPP-45142 is a NANOBODY-based HER2-targeting TCE built on a T-cell receptor αβ framework. It binds a HER2 epitope distinct from trastuzumab and pertuzumab and redirects T cells to kill HER2-low cancers.\"},{\"question\":\"How does TPP-45142 perform in preclinical settings?\",\"answer\":\"TPP-45142 mediates potent T cell–dependent cytotoxicity against HER2-low cancer cell lines in vitro. It also inhibits in vivo tumor growth of HER2-low breast cancer xenografts.\"},{\"question\":\"Why is selectivity and safety important for TCEs like TPP-45142?\",\"answer\":\"Solid-tumor targeting can produce on-target, off-tumor adverse effects when antigens are also present in healthy organs. TPP-45142 shows high selectivity for low-HER2 tumor cells versus normal cardiac cells and demonstrates a favorable therapeutic index based on a cytokine release assay.\"}]","TPP-45142 - an Anti-HER2 T-cell Engager - Designed for Selective HER2-Low Cancer Immunotherapy | PDF",1790126061,38]