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AMT-562 was engineered from a novel anti-HER3 antibody (Ab562) and a modified self-immolative PABC spacer (T800) conjugated to exatecan. In low-HER3 and heterogeneous xenograft/PDX/organoid models, AMT-562 produced potent, durable antitumor effects, with favorable pharmacokinetic and safety profiles, including the highest tested tolerated dose. Combination regimens exhibited stronger synergy than Patritumab-GGFG-DXd, supporting AMT-562’s potential to overcome resistance.",{"@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/amt-562-a-novel-her3-targeting-antibodydrug-conjugate-demonstrates-a-potential-to-broaden-therapeutic-opportunities-for-her3-expressing-tumors/380380/",{"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/amt-562-a-novel-her3-targeting-antibodydrug-conjugate-demonstrates-a-potential-to-broaden-therapeutic-opportunities-for-her3-expressing-tumors/380380.png","ImageObject",300,407,{"name":92,"@type":93},"Bintang","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is HER3 a challenging therapeutic target?","Question",{"text":112,"@type":113},"HER3 is broadly expressed and linked to poor outcomes and resistance, but it cannot be inhibited effectively by classical ATP-analog kinase inhibitors. Blocking generally requires targeting its extracellular domain with antibodies or antibody-based therapeutics.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How is AMT-562 constructed and what drug does it deliver?",{"text":117,"@type":113},"AMT-562 combines a novel anti-HER3 antibody (Ab562) with a modified self-immolative PABC spacer (T800) conjugated to exatecan. The design uses exatecan to achieve higher cytotoxic potency than a related derivative.",{"name":119,"@type":110,"acceptedAnswer":120},"What evidence supports AMT-562’s potential to improve outcomes versus U3-1402?",{"text":121,"@type":113},"AMT-562 shows potent and durable antitumor responses in low-HER3 expression xenografts and heterogeneous patient-derived models, including digestive system and lung tumors. It also demonstrates stronger or synergistic effects in combination settings and has favorable pharmacokinetic and safety profiles, suggesting an improved therapeutic window.","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},380380,1790314708,{"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":34,"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},962085564381,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","FIRST DISCLOSURE  \nAMT-562, a Novel HER3-targeting Antibody–Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors Weining Weng1,2, Tao Meng3,4, Junyi Pu5, Linjie Ma2, Yi Shen2, Zhaohui Wang6, Rong Pan6, Mingqiao Wang6, Caiwei Chen2, Lijun Wang2, Jianjian Zhang2, Biao Zhou2, Siyuan Shao7, Yu Qian1,  \nShuhui Liu2, Wenhao Hu1, and Xun Meng2,6  \nABSTRACT  \n\n| ◥ | HER3 is a unique member of the EGFR family of tyrosine kinases, which is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancersand is often associated with poor patient outcomes and therapeutic resistance. U3-1402/Patritumab-GGFG-DXd is the first successful HER3-targeting antibody–drug conjugate (ADC) with clinical efficacyin non–small cell lung cancer. However, over60% ofpatients are nonresponsive to U3-1402 due to low target expression levels and responses tend to be in patients with higher target expression levels. U3-1402 is also ineffective in more challenging tumor types such as colorectal cancer. AMT-562 was generated by a novel anti-HER3 antibody Ab562and a modified self-immolative PABC spacer(T800) to conjugate exatecan. Exatecan showed higher cytotoxic potency than its derivative DXd. Ab562 was selected because of its moderate affinity for minimizing potential toxicity and improving tumor penetration purposes. Both alone or in combination therapies, AMT-562 showed potent and durable antitumor response in low HER3 expression xenograft and heterogeneous patient-derived xenograft/ organoid models, including digestive system and lung tumors representing of unmet needs. Combination therapies pairing AMT-562 | with therapeutic antibodies, inhibitors of CHEK1, KRAS, and tyrosine kinase inhibitor showed higher synergistic efficacy than Patritumab-GGFG-DXd. Pharmacokinetic and safety profiles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg incynomolgus monkeys. AMT-562 has potential tobea superior HER3-targeting ADC with a higher therapeutic window that can overcome resistance to generate higher percentage and more durable responses in U3-1402–insensitive tumors. |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- |\n|  |  | MC VA T moiety Exatecan Exatecan |  |  | 1500\u003Cbr>1000\u003Cbr>500\u003Cbr>00-20-40 -60 -80 -100 | |\n|  |  | |  | |  |  |\n|  |  | AMT-562: a HER3-targeting ADC using TOP I inhibitor exatecan |  | |  |  |\n|  |  |  |  |  | A549 PC9 H1975 H2170 361019 390629 200730 361646 200717 200662\u003Cbr>AMT-562 shows superior efficacy to P-GGFG-DXd in NSCLC |  |\n|  |  | 800\u003Cbr>600\u003Cbr>400\u003Cbr>200\u003Cbr>0\u003Cbr>-200\u003Cbr>|  |  |  |  |\n|  |  | AMT-562 is more effective in CRC | AMT-562 demonstrates stronger synergy in CRC |  |  |  |\n\nT800： X=CH2-NH-CH3  \nTumor volume change from baseline (%)  \nTumor volume (mm3)  \n(mean±SEM)  \nTumor volume change from baseline (%)  \nKRAS G12C  \nBRA F V600E  \nCD74-ROS1 fusion ROS1 G2032R  \nTP53 R158G  \nTP53 R273H PI K3CA G118D  \nKRAS G12S  \n****p\u003C0. 0001  \n**p 0.0028  \nIntroduction  \nHER3 is a unique member of the EGFR family of tyrosine kinases (ErbB; refs. 1, 2). It is a pseudokinase lacking significant kinase activity and requires heterodimerization with other members of ErbB family to activate downstream signaling pathways (1, 3, 4). HER3 is broadly expressed in solid tumors such as breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers and is often associated with  \n1Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, P. R. China. 2Multitude Therapeutics, Shanghai, P. R. China. 3MabCare Therapeutics, Shanghai, P. R. China. 4HySlink Therapeutics, Shanghai, P. R. China. 5School of Life Sciences, Northwest University, Xi’an, Shaanxi, P. R. China. 6Abmart Inc, Shanghai, P. R. China. 7Shanghai OneTar Biomedicine, Shanghai, P. R. China.  \nCorresponding Authors: Xun Meng, Multitude Therapeutics, 3rd floor Bui","cbCaia2jkXfAdfAZ","https://ap.wps.com/l/cbCaia2jkXfAdfAZ","pdf",13400719,15,"English","# Abstract\n## HER3 and therapeutic challenges\n## AMT-562 design and mechanism\n## Preclinical efficacy and model types\n## Combination strategies and results\n## Pharmacokinetics and safety","[{\"question\":\"Why is HER3 a challenging therapeutic target?\",\"answer\":\"HER3 is broadly expressed and linked to poor outcomes and resistance, but it cannot be inhibited effectively by classical ATP-analog kinase inhibitors. Blocking generally requires targeting its extracellular domain with antibodies or antibody-based therapeutics.\"},{\"question\":\"How is AMT-562 constructed and what drug does it deliver?\",\"answer\":\"AMT-562 combines a novel anti-HER3 antibody (Ab562) with a modified self-immolative PABC spacer (T800) conjugated to exatecan. The design uses exatecan to achieve higher cytotoxic potency than a related derivative.\"},{\"question\":\"What evidence supports AMT-562’s potential to improve outcomes versus U3-1402?\",\"answer\":\"AMT-562 shows potent and durable antitumor responses in low-HER3 expression xenografts and heterogeneous patient-derived models, including digestive system and lung tumors. It also demonstrates stronger or synergistic effects in combination settings and has favorable pharmacokinetic and safety profiles, suggesting an improved therapeutic window.\"}]","AMT-562, a Novel HER3-targeting Antibody–Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors | PDF",1790239962,38]