A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer
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 (...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-07-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/8/2020 |
| _version_ | 1797583520165527552 |
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| author | Candice Maria Mckertish Veysel Kayser |
| author_facet | Candice Maria Mckertish Veysel Kayser |
| author_sort | Candice Maria Mckertish |
| collection | DOAJ |
| description | 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 (Tmab-VcMMAE) was conjugated with a second antimitotic agent, Mertansine (DM1), via a non-cleavable linker Succinimidyl-4-(<i>N</i>-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) to form a dual conjugate (Tmab-VcMMAE-SMCC-DM1). Our results indicated that the dual-payload conjugate, Tmab-VcMMAE-SMCC-DM1, had a synergistic and superior cytotoxic effect compared to trastuzumab alone. Ultimately employing a dual conjugation approach has the potential to overcome treatment-resistance and tumour recurrences and could pave the way to employ other payloads to construct dual (or multiple) payload complexes. |
| first_indexed | 2024-03-10T23:40:05Z |
| format | Article |
| id | doaj.art-f3a82f403e674b09bff1a6b125fb8765 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T23:40:05Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-f3a82f403e674b09bff1a6b125fb87652023-11-19T02:35:28ZengMDPI AGPharmaceutics1999-49232023-07-01158202010.3390/pharmaceutics15082020A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon CancerCandice Maria Mckertish0Veysel Kayser1Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaSydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, AustraliaAntibody-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 (Tmab-VcMMAE) was conjugated with a second antimitotic agent, Mertansine (DM1), via a non-cleavable linker Succinimidyl-4-(<i>N</i>-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) to form a dual conjugate (Tmab-VcMMAE-SMCC-DM1). Our results indicated that the dual-payload conjugate, Tmab-VcMMAE-SMCC-DM1, had a synergistic and superior cytotoxic effect compared to trastuzumab alone. Ultimately employing a dual conjugation approach has the potential to overcome treatment-resistance and tumour recurrences and could pave the way to employ other payloads to construct dual (or multiple) payload complexes.https://www.mdpi.com/1999-4923/15/8/2020antibody drug conjugatesADCsantimitoticmicrotubule polymerizationVcMMAESMCC-DM1 |
| spellingShingle | Candice Maria Mckertish Veysel Kayser A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer Pharmaceutics antibody drug conjugates ADCs antimitotic microtubule polymerization VcMMAE SMCC-DM1 |
| title | A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer |
| title_full | A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer |
| title_fullStr | A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer |
| title_full_unstemmed | A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer |
| title_short | A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer |
| title_sort | novel dual payload adc for the treatment of her2 breast and colon cancer |
| topic | antibody drug conjugates ADCs antimitotic microtubule polymerization VcMMAE SMCC-DM1 |
| url | https://www.mdpi.com/1999-4923/15/8/2020 |
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