Expanding the payload scope in antibody-drug conjugates by delivery of hydroxy-containing drugs through self-immolative phosphoramidates
Despite recent advances in targeted drug delivery, approved Antibody-Drug-Conjugates (ADCs) are still limited by the delivery of a restricted set of payloads with limited modes of action (MOA). Versatile linkers, applicable to functional groups prevalent across diverse pharmacophores are needed to expand this space. We present phosphoramidate-based self-immolative linker-units that facilitate stable attachment in serum and traceless drug release in the target cell of aliphatic and aromatic alcohols. Studies with camptothecins show that stability and release are tunable and that various intracellular trigger events can be exploited to ensure traceless drug delivery. Superior stability, in vivo efficacy, and pharmacokinetics (PK) compared to approved camptothecin ADCs are demonstrated. Moreover, we report targeted delivery of 10 different hydroxy-containing cytotoxins with different intracellular MOAs. In vivo studies with gemcitabine show excellent PK and efficacy, unlocking gemcitabine's full potential and illustrating the ability of the phosphoramidate-based linker system to expand the payload space for ADCs.
Authors
- Isabelle Mai (ORCID: https://orcid.org/0009-0002-1574-2683)
- Marc‐André Kasper (ORCID: https://orcid.org/0000-0001-7742-7465)
- Sarah Herterich (ORCID: https://orcid.org/0009-0001-7391-3199)
- Philipp Cyprys (ORCID: https://orcid.org/0009-0000-2412-5551)
- Jan G. Felber (ORCID: https://orcid.org/0000-0002-5010-9624)
- Dominik Schumacher (ORCID: https://orcid.org/0000-0001-7095-6858)
- Anil P. Jagtap
- Jonas Helma (ORCID: https://orcid.org/0000-0001-6158-452X)
- Saskia Schmitt (ORCID: https://orcid.org/0009-0003-1362-9158)
- Annette M. Vogl (ORCID: https://orcid.org/0000-0001-6283-2521)
- Philipp Ochtrop (ORCID: https://orcid.org/0000-0003-4498-3136)
- Swetlana Wunder (ORCID: https://orcid.org/0009-0007-5578-4008)
- Annabel Kitowski (ORCID: https://orcid.org/0000-0002-8001-5928)
- Paul Machui (ORCID: https://orcid.org/0009-0006-7772-2361)
- Simon Vogt
- Julia Ines Brandmeier
- Sarah Payer
- Elizaveta Poliak
- Natascia Leonardi
- Christian P. R. Hackenberger
- Olivier Marcq
Institutions
- MorphoSys (Germany) (DE)
- Humboldt-Universität zu Berlin (DE)
- Universidade do Sul de Santa Catarina (BR)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-20
- DOI
- https://doi.org/10.1038/s41467-026-68605-y
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ludwig-Maximilians-Universität München