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This study designs a dual-payload ADC by attaching two different antimitotic agents to different amino acid residues on trastuzumab: MMAE via the cleavable Val-Cit linker, followed by DM1 using the non-cleavable SMCC linker. The resulting dual conjugate shows synergistic, superior cytotoxic effects compared with trastuzumab alone, suggesting dual conjugation may help address resistance and recurrence and enable future multi-payload constructs.",{"@graph":69,"@context":123},[70,84,106],{"@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/a-novel-dual-payload-adc-for-the-treatment-of-her2-breast-and-colon-cancer/381517/",{"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/a-novel-dual-payload-adc-for-the-treatment-of-her2-breast-and-colon-cancer/381517.png","ImageObject",300,407,{"name":92,"@type":93},"Melati","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the goal of the novel dual-payload ADC design?","Question",{"text":113,"@type":114},"To achieve maximal therapeutic effects by combining two distinct cytotoxic payloads on trastuzumab so the ADC can act more powerfully against HER2+ breast and colon cancer cells.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How are the two payloads attached to trastuzumab in this study?",{"text":118,"@type":114},"MMAE is conjugated through a cleavable Val-Cit linker to cysteine residues, and DM1 is conjugated via the non-cleavable SMCC linker to lysine residues.",{"name":120,"@type":111,"acceptedAnswer":121},"What results are reported for the dual-payload conjugate compared with trastuzumab alone?",{"text":122,"@type":114},"The dual-payload conjugate demonstrates a synergistic and superior cytotoxic effect compared with trastuzumab alone.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},381517,1790673766,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},962085570644,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","pharmaceutics  \nArticle  \nA Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer  \nCandice Maria Mckertish  and Veysel Kayser *  \nCitation: Mckertish, C.M.; Kayser, V. A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer. Pharmaceutics 2023, 15, 2020. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)pharmaceutics15082020  \nAcademic Editor: Isabelle Turbica  \nReceived: 30 June 2023  \nRevised: 14 July 2023  \nAccepted: 24 July 2023  \nPublished: 26 July 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \nSydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia  \n* [Correspondence: veysel.kayser@sydney.edu.au](Correspondence: veysel.kayser@sydney.edu.au); Tel.: +61-2-9351-3391  \nAbstract: Antibody-drug conjugates (ADCs) have demonstrated a great therapeutic potential against cancer due to their target specificity and cytotoxicity. To exert a maximum therapeutic effect on cancerous cells, we have conjugated two different payloads to different amino acids, cysteines (cys) and lysines (lys), on trastuzumab, which is a humanised anti-HER2 monoclonal antibody. First, trastuzumab was conjugated with monomethyl auristatin E (MMAE), an antimitotic agent, through a cleavable linker (Val-Cit) to prepare ADC (Tmab-VcMMAE) . Then, the ADC (TmabVcMMAE) was conjugated with a second antimitotic agent, Mertansine (DM1), via a non-cleavable linker Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) to form a dual conjugate (Tmab-VcMMAE-SMCC-DM1) . Our results indicated that the dual-payload conjugate, TmabVcMMAE-SMCC-DM1, had a synergistic and superior cytotoxic effect compared to trastuzumabalone. Ultimately employing a dual conjugation approach has the potential to overcome treatmentresistance and tumour recurrences and could pave the way to employ other payloads to construct dual (or multiple) payload complexes.  \nKeywords: antibody drug conjugates; ADCs; antimitotic; microtubule polymerization; VcMMAE; SMCC-DM1; SK-BR-3; DLD-1; cytotoxic assay; trastuzumab; target specific  \n1. Introduction  \nAntibody-drug conjugates (ADCs) have generated great interest for the treatment of cancer. ADCs have demonstrated superior effects over standard chemotherapy agents for cancer due to their target specificity and efficacy [1] . Our study aimed at using a novel dual-payload ADC construct to target cancers that express the HER2+ antigen specificallyin breast and colon cancer. The biomarker human epidermal growth factor receptor 2 (HER2) is expressed in some cancers, such as breast and colon cancer, but at different levels [2] . Gene amplification of the HER2 protein causes overexpression, resulting in higher-than-normal levels of the HER2 protein in cancerous cells [3] .  \nBreast cancer is one of the most-diagnosed cancers globally according to the World Health Organization (WHO) [4,5] . Globally in 2020, breast cancer accounted for approximately more than 6.5% of mortalities and more than 11.5% of newly diagnosed cases of all cancer types [6], and colon cancer ranks third as the most common type of cancer and second as the most common cause of mortality worldwide compared to other cancer types [5] . Although a lot of progress has been made in recent years, targeted therapy is a rapidly evolving field and several ADCs have been approved.  \nAs of December 2021, eleven ADCs have been approved by the US Food and Drug Administration (FDA), ten by the European Medicines Agency (EMA), and six by the Australian Therapeutic Goods Administration (TGA) . Some of these ADCs have been developed for the treatment of various t","cbCaiou8ZgLZglgR","https://ap.wps.com/l/cbCaiou8ZgLZglgR","pdf",5090049,17,"English","# Abstract\n# Keywords\n# Introduction","[{\"question\":\"What is the goal of the novel dual-payload ADC design?\",\"answer\":\"To achieve maximal therapeutic effects by combining two distinct cytotoxic payloads on trastuzumab so the ADC can act more powerfully against HER2+ breast and colon cancer cells.\"},{\"question\":\"How are the two payloads attached to trastuzumab in this study?\",\"answer\":\"MMAE is conjugated through a cleavable Val-Cit linker to cysteine residues, and DM1 is conjugated via the non-cleavable SMCC linker to lysine residues.\"},{\"question\":\"What results are reported for the dual-payload conjugate compared with trastuzumab alone?\",\"answer\":\"The dual-payload conjugate demonstrates a synergistic and superior cytotoxic effect compared with trastuzumab alone.\"}]","A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer | PDF",1790245651,43]