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© 2025 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://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Details

Title
Understanding the Toxicity Profile of Approved ADCs
Author
Ballestín, Pablo 1   VIAFID ORCID Logo  ; López de Sá, Alfonso 1 ; Díaz-Tejeiro, Cristina 1 ; Paniagua-Herranz, Lucía 1 ; Sanvicente, Adrián 1   VIAFID ORCID Logo  ; López-Cade, Igor 1 ; Pérez-Segura, Pedro 1 ; Alonso-Moreno, Carlos 2   VIAFID ORCID Logo  ; Nieto-Jiménez, Cristina 1   VIAFID ORCID Logo  ; Ocaña, Alberto 3   VIAFID ORCID Logo 

 Experimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, Spain 
 Unidad 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, Spain 
 Experimental Therapeutics Unit, Departamento Oncología Médica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), 28040 Madrid, Spain; Centro de Investigación Biomédica en Red en Oncología (CIBERONC), 28029 Madrid, Spain 
First page
258
Publication year
2025
Publication date
2025
Publisher
MDPI AG
e-ISSN
19994923
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3171178814
Copyright
© 2025 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://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.