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Review
. 2025 Sep;174(3):541-556.
doi: 10.1007/s11060-025-05083-0. Epub 2025 Jun 5.

Antibody drug conjugates in metastatic brain tumors: current landscape, therapeutic potential and challenges

Stephanie M Robert  1 , Allison Toth  1 , Sapir Lev  1 , Stephen G Bowden  1 , Yao Yu  2 , Brandon S Imber  2   3 , Adrienne Boire  4 , Joshua Z Drago  5 , Shanu Modi  5 , Nelson S Moss  6   7   8
Affiliations
Review

Antibody drug conjugates in metastatic brain tumors: current landscape, therapeutic potential and challenges

Stephanie M Robert et al. J Neurooncol. 2025 Sep.

Abstract

The management of brain metastases (BrM) remains a major clinical challenge due to limited drug delivery across the blood-brain barrier (BBB) and the need for simultaneous CNS and systemic disease management, often with competing therapeutic strategies. Antibody-drug conjugates (ADCs) are a promising class of drugs that offers precision therapy by combining the specificity of monoclonal antibodies with potent chemotherapeutics for targeted tumor delivery. This review explores the current landscape of ADCs in BrMs, challenges in BBB penetration, and CNS-specific toxicities, including interactions with radiotherapy and the risk of radiation necrosis.

Keywords: Antineoplastic agents; Blood-brain barrier; Brain neoplasms; Immunoconjugates; Necrosis; Tumor microenvironment.

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Conflict of interest statement

Declarations. Competing interests: Financial Interests: SMR, AT, SL, SGB declare that they have no financial interest. Y.Y. has received funding from EMD Serono. B.S.I reports research grants (to institution) from Novartis, Kazia Therapeutics, GT Medical Technologies, AstraZeneca, and Bayer outside the submitted work and serves as a consultant to GT Medical Technologies. A.B. is a Consultant for Arix Biosciences, and has patents related to methods for treating brain metastasis (US Patent 10,413,522) and modulating permeability of the blood–CSF barrier (US Provisional Application Number 62/258,044. J.D. receives funding and honoraria from the following: Intellisphere LLC (Honoraria for talks), AZ (Research Funding AND Consulting), Genagon (Consulting), AmMax Bio (Consulting), NuProbe (Consulting), Revelio Therapeutics (Consulting), MEDACorp (Consulting), Merck (Research Funding), Baird Conferences (Consulting). S.M. received institutional research support from Genentech, Astra Zeneca, Seattle Genetics, Pfizer, Daiichi Sankyo, Duality Bio, D3 Bio, Nuvation Bio, BioNTech; and is a scientific consultant/advisor/speaker for Daiichi Sankyo, Eli Lilly, Genentech, Gilead, Macrogenics, Glaxo-Smith Kline, Seattle Genetics, Pfizer, Gilead, BMS, Nuvation Bio, D3 Bio, AstraZeneca, BioNTech, Boehringer Ingelheim, Avacta. N.S.M receives honoraria from Daiichi Sankyo and Varian, consulting fees from AstraZeneca, and research funding (to institution) from AstraZeneca, Amgen, GT Medical Technologies.

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