Pharmacology and pharmacokinetics of antibody-drug conjugates, where do we stand?
- PMID: 40157134
- DOI: 10.1016/j.ctrv.2025.102922
Pharmacology and pharmacokinetics of antibody-drug conjugates, where do we stand?
Abstract
Antibody-drug conjugates (ADCs) are a rising therapeutic class in oncology and hematology, with eleven drugs approved by the US Food and Drug Administration as of January 2025. These "magic bullets" have a complex structure, including a monoclonal antibody, a linker, attachment sites, and a payload usually disrupting microtubules, targeting DNA, or inhibiting topoisomerase 1. By targeting specific tumor antigens, they are expected to be exquisitely effective in releasing "supertoxic" payloads inside tumor cells after intracellular trafficking. Additionally, they may exert a bystander effect, wherein the released payloads act on neighboring cells, amplifying their therapeutic impact regardless of target expression. ADCs have been game-changing drugs to treat tumors with once dismal prognoses or with previously considered unactionable targets, such as HER2-low or triple-negative breast cancer. To what extent there is room for personalized medicine to improve the toxicity/efficacy ratio remains unknown. However, there are inherent issues related to the complexity of the pharmacokinetics of ADCs and their assessments: efficacy or toxicity may be influenced by the clearance of the intact ADC, the circulating payload, or the payload-linker complex. Deciphering these multifaceted exposure-outcomes relationships for both efficacy and safety endpoints, is critical for advancing precision medicine and enabling personalized dosing strategies. To improve future developments and broaden their therapeutic scope, several strategies can be developed, including developing adequate combinations with other treatment classes (cytotoxic agents, immune-checkpoint inhibitors, oral molecular-targeted therapies). In this review, we will discuss the PK/PD aspects of ADCs and their dosing to improve their use in current and future indications.
Keywords: Antibody-dug conjugate (ADC); Exposure-efficacy relationship (EER); Exposure-safety relationship (ESR); Pharmacodynamics; Pharmacokinetics; Therapeutic drug monitoring (TDM).
Copyright © 2025 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Arthur Géraud: Astra Zeneca (congress invitation), EISAI (congress invitation), Gilead (congress invitation, lecture fees), Lilly (congress invitation, lecture fees), Luzsana (consulting fees), Novartis (congress invitation), Pfizer (congress invitation), Promise Proteomics (consulting fees) Paul Gougis: BMS (consulting fees), EISAI (congress accommodation), Sanofi (academic grant) Alexandre de Nonneville: Gilead (consulting fees, lecture fees, congress invitations), Daiichi Sankyo (consulting fees, lecture fees, congress invitations), Astra Zeneca (consulting fees, lecture fees, congress invitations), Seagen (consulting fees), Lilly (consulting fees, lecture fees, congress invitations), Novartis (consulting fees, lecture fees, congress invitations), MSD (consulting fees, congress invitations, lecture fees), Pfizer (research grants paid to institution, lecture fees, congress invitations), Promise Proteomics (consulting fees). Mathilde Beaufils: Pfizer (meeting registrations). Fabrice Bertucci: no competing interest related to this manuscript Emilien Billon: no competing interest related to this manuscript Gabriel Brisou: Abbvie (consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events), BMS (consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, Support for attending meetings and/or travel, Participation on a Data Safety Monitoring Board or Advisory Board), Incite (consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, Support for attending meetings and/or travel), Kite Gilead (consulting fees, Support for attending meetings and/or travel), Miltenyi Biomedecine (Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events ), Novartis (consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, Support for attending meetings and/or travel), Roche (consulting fees) Gwenael Gravis: BMS, Janssen (Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events honoraria to her institution). Astra Zeneca, AMGEN, Astellas, BAYER, EISAI, IPSEN, Pfizer, Alliance Merck-Pfizer, MSD, Novartis (support for attending meetings and/or travel). Alliance Merck-Pfizer, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Novartis and Pfizer (data safety monitoring board or advisory board paid to her institution). Laurent Greillier: Abbvie (consulting fees), Amgen (congress invitation, lecture fees, consulting fees), Astra Zeneca (congress invitation, lecture fees), Bristol Myers Squibb (lecture fees, consulting fees), Daiichi Sankyo (consulting fees), Eli Lilly Oncology (consulting fees), MSD (congress invitation, lecture fees, consulting fees), Novartis (consulting fees), Novocure (consulting fees) Pharmamar (lecture fees), Pfizer (congress invitation, lecture fees, consulting fees), Promise Proteomics (consulting fees), Regeneron (lecture fees), Roche (Sanofi (lecture fees, consulting fees) Takeda (congress invitation, lecture fees, consulting fees). Mathilde Guerin: Ipsen (Boards, consulting fees), MSD (congress invitation), Pfizer (consulting fees, congress invitation) Emmanuel Mitry: no competing interest related to this manuscript Robin Noel : Takeda (congress invitation) Johnson and Johnson (congress invitation) Josephine Pignon: nothing to declare Renaud Sabatier: Astra Zeneca (research grants paid to institution, speaker bureaus, meeting registration), Pfizer (speaker bureau), Novartis (speaker bureau, meeting registration), MSD (consulting fees, meeting registration), GSK (consulting fees, speaker bureaus, meeting registration), EISAI (speaker bureau, meeting registrations). LS: AstraZeneca (lecture fees), Sivan (lecture fees), MSD (lecture fees), Lilly (meeting registration), Pfizer (meeting registrations), Novartis (meeting registration). JPS: AstraZeneca (consulting fees), Daichy-Sankyo (Adlb board), Exact Science (Adbloard), Gilead (Adbloard), Incyte (consulting fees), Lilly (Adbloard), MSD (consulting fees), MSD avenir (Grant), Novaris Pfizer (Adbloard) Cécile Vicier: Novartis (travel expenses, consulting fees), Pfizer (travel expenses, consulting fees, lecture fees), BMS (lecture fees), Seagen (lecture fees), Ipsen (lecture fees, travel expenses), Daiichi Sankyo (consulting fees, lecture fees), Astra Zeneca (consulting fees) Frederic Viret: nothing to declare Anthony Goncalves: Astra Zeneca (Grants, Participation on a Data Safety Monitoring Board or Advisory Board), Daiichi Sankyo (Grants), Gilead (Grants, Participation on a Data Safety Monitoring Board or Advisory Board), Menarini (Support for attending meetings and/or travel), Mylan (Support for attending meetings and/or travel), MSD (Participation on a Data Safety Monitoring Board or Advisory Board), Novartis (Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational, Grants, Participation on a Data Safety Monitoring Board or Advisory Board), Roche/Genentech (Grants). Joseph Ciccolini: Pierre Fabre (lecture fees), Pfizer (Board), Merck Serono (Board), Daiichi Sankyo (lecture fees), Servier (lecture fees), Pierre Fabre (travel grant)
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