Aug 2026· Bioconjugate chemistry· Vol 37, pp. 1798-1803· 0 citations· 29 references
TL;DR
Observations around LogD, pKa, permeability, permeability, efflux, and metabolic stability are discussed and design rules and guidelines for the optimization of next-generation ADC payloads are suggested.
Abstract
Despite significant research and investment, antibody–drug conjugates (ADCs) primarily rely on a limited number of broadly cytotoxic payloads that contribute significantly to toxicity. More recently, there has been a migration toward mechanistically targeted payloads, pairing improved antibodies with small molecules that act on disease-specific biology, improving precision and tolerability. Designing these next-generation payloads means rethinking some of our design metrics and guidelines derived from traditional medicinal chemistry: properties such as LogD, pKa, permeability, efflux, and metabolic stability must be carefully balanced to ensure efficient intracellular release while limiting systemic exposure. Here we discuss our observations around these properties and suggest design rules and guidelines for the optimization of next-generation ADC payloads.
Abstract Conventional antibody–drug conjugates (ADCs) are typically limited to drug-to-antibody ratios (DARs) of ≤8 because of restricted conjugation sites and unfavorable physicochemical properties at higher DARs, including increased hydrophobicity, aggregation, and rapid systemic clearance. Consequently, most clinica...
Hao-Sheng Feng, Bin Liu· Antibody Therapeutics· 0 citations
The biological basis and translational challenges of de novo and acquired resistance related to targets, payloads, and tumor microenvironmental constraints, as well as the implications of these mechanisms for biomarker development, sequencing rationales, and combination strategies with immune checkpoint inhibitors and...
Chen-Xu Guo, L. Ellisen· Journal of Clinical Investig...· 0 citations
The principles of ADCs linkers are reviewed and perspectives on the challenges and innovative approaches to the future ADC drug development are shared, highlighting both established and emerging design principles and elucidating key structure-function relationships governing ADC stability, pharmacokinetics, and control...
Xing-Quan Ma, Bing Li, Yao Ma et al.· Journal of Controlled Releas...· 0 citations
Covalent small-molecule drugs have re-emerged as an important class of targeted therapeutics because they can sustain target engagement and exploit nucleophilic residues inaccessible to reversible ligands. However, covalent pharmacology has historically been constrained by concerns about nonspecific reactivity and limi...
John-Paul Ong, Montana Dalziel, Dona Johns et al.· Drug Discovery Today· 0 citations
Drug–drug conjugates (DDCs), in which two active pharmaceutical ingredients (APIs) are linked covalently within a single molecular structure to produce a synergistic therapeutic effect, represent an emerging category of single-molecule therapeutics. These conjugates differ from conventional combination therapies by uti...
A. Abufara, M. A. Mousa, Hamdi Nsairat· Biomolecules· 0 citations
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