Understanding the Toxicity Profile of Approved ADCs
<b>Background:</b> Antibody–drug conjugates (ADCs) represent a novel therapeutic class that combines an antibody against a tumor-associated antigen (TAA), a payload, and a linker that binds these two components. Serious adverse events (SAEs), particularly those of grade 3 (G3) or higher,...
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2025-02-01
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| Online Access: | https://www.mdpi.com/1999-4923/17/2/258 |
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| author | Pablo Ballestín Alfonso López de Sá Cristina Díaz-Tejeiro Lucía Paniagua-Herranz Adrián Sanvicente Igor López-Cade Pedro Pérez-Segura Carlos Alonso-Moreno Cristina Nieto-Jiménez Alberto Ocaña |
| author_facet | Pablo Ballestín Alfonso López de Sá Cristina Díaz-Tejeiro Lucía Paniagua-Herranz Adrián Sanvicente Igor López-Cade Pedro Pérez-Segura Carlos Alonso-Moreno Cristina Nieto-Jiménez Alberto Ocaña |
| author_sort | Pablo Ballestín |
| collection | DOAJ |
| description | <b>Background:</b> Antibody–drug conjugates (ADCs) represent a novel therapeutic class that combines an antibody against a tumor-associated antigen (TAA), a payload, and a linker that binds these two components. Serious adverse events (SAEs), particularly those of grade 3 (G3) or higher, frequently contribute to the abandonment of ADCs during clinical development. <b>Methods:</b> In this study, we analyzed the toxicity profiles of all approved ADCs, aiming to uncover correlations between their safety profiles and the specific characteristics of their components. <b>Results:</b> In our analysis, dose reductions, dose delays, treatment discontinuations, and ≥G3 toxicities were not significantly different across payload types. Similarly, no association was found between the payload mechanism of action and ≥G3 toxicities, including anemia, neutropenia, febrile neutropenia, thrombocytopenia, and diarrhea. By exploring the specific toxicities of ADCs observed by organ, we identified that most were related to the payload mechanism of action, like the ≥G3 diarrhea observed in 10% of patients treated with sacituzumab govitecan (the payload SN-38 is the active metabolite of irinotecan), and very few were related to the presence of the TAA in normal tissue (presence of Nectin-4 in skin and ≥G3 rash toxicity in 14% of patients treated with enfortumab vedotin). In line with this, no major differences in ≥G3 toxicities were identified in studies with different levels of the TAA (trastuzumab deruxtecan in Destiny Breast Studies with different HER2 expression levels). <b>Conclusions:</b> Our analysis reveals that most ADC toxicities are driven by the payload’s effects on non-transformed tissues; however, a detailed analysis of each ADC component should be taken into consideration. |
| format | Article |
| id | doaj-art-475e9f6a8a864550bbe111a2f7b5b2bb |
| institution | DOAJ |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-475e9f6a8a864550bbe111a2f7b5b2bb2025-08-20T02:44:54ZengMDPI AGPharmaceutics1999-49232025-02-0117225810.3390/pharmaceutics17020258Understanding the Toxicity Profile of Approved ADCsPablo Ballestín0Alfonso López de Sá1Cristina Díaz-Tejeiro2Lucía Paniagua-Herranz3Adrián Sanvicente4Igor López-Cade5Pedro Pérez-Segura6Carlos Alonso-Moreno7Cristina Nieto-Jiménez8Alberto Ocaña9Experimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, SpainExperimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, SpainExperimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, SpainExperimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, SpainExperimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, SpainExperimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, SpainExperimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, SpainUnidad nanoDrug, Centro de Innovación en Química Avanzada (ORFEO-CINQA), Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Farmacia, Universidad de Castilla-La Mancha, 02071 Albacete, SpainExperimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, SpainExperimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, Spain<b>Background:</b> Antibody–drug conjugates (ADCs) represent a novel therapeutic class that combines an antibody against a tumor-associated antigen (TAA), a payload, and a linker that binds these two components. Serious adverse events (SAEs), particularly those of grade 3 (G3) or higher, frequently contribute to the abandonment of ADCs during clinical development. <b>Methods:</b> In this study, we analyzed the toxicity profiles of all approved ADCs, aiming to uncover correlations between their safety profiles and the specific characteristics of their components. <b>Results:</b> In our analysis, dose reductions, dose delays, treatment discontinuations, and ≥G3 toxicities were not significantly different across payload types. Similarly, no association was found between the payload mechanism of action and ≥G3 toxicities, including anemia, neutropenia, febrile neutropenia, thrombocytopenia, and diarrhea. By exploring the specific toxicities of ADCs observed by organ, we identified that most were related to the payload mechanism of action, like the ≥G3 diarrhea observed in 10% of patients treated with sacituzumab govitecan (the payload SN-38 is the active metabolite of irinotecan), and very few were related to the presence of the TAA in normal tissue (presence of Nectin-4 in skin and ≥G3 rash toxicity in 14% of patients treated with enfortumab vedotin). In line with this, no major differences in ≥G3 toxicities were identified in studies with different levels of the TAA (trastuzumab deruxtecan in Destiny Breast Studies with different HER2 expression levels). <b>Conclusions:</b> Our analysis reveals that most ADC toxicities are driven by the payload’s effects on non-transformed tissues; however, a detailed analysis of each ADC component should be taken into consideration.https://www.mdpi.com/1999-4923/17/2/258antibody–drug conjugateantibodytoxicitypayload |
| spellingShingle | Pablo Ballestín Alfonso López de Sá Cristina Díaz-Tejeiro Lucía Paniagua-Herranz Adrián Sanvicente Igor López-Cade Pedro Pérez-Segura Carlos Alonso-Moreno Cristina Nieto-Jiménez Alberto Ocaña Understanding the Toxicity Profile of Approved ADCs Pharmaceutics antibody–drug conjugate antibody toxicity payload |
| title | Understanding the Toxicity Profile of Approved ADCs |
| title_full | Understanding the Toxicity Profile of Approved ADCs |
| title_fullStr | Understanding the Toxicity Profile of Approved ADCs |
| title_full_unstemmed | Understanding the Toxicity Profile of Approved ADCs |
| title_short | Understanding the Toxicity Profile of Approved ADCs |
| title_sort | understanding the toxicity profile of approved adcs |
| topic | antibody–drug conjugate antibody toxicity payload |
| url | https://www.mdpi.com/1999-4923/17/2/258 |
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