Antibody–drug conjugates (ADCs) have emerged as a powerful class of targeted therapeutics in many clinical areas, such as in oncology. Despite their efficacy, the onset of adverse events has been a major drawback in their clinical use. Among other explanations, the clinical performance of the ADCs has been associated with the chemistry of the linker connecting the antibody and payload. Linkers determine plasma stability, intracellular activation, and payload diffusibility, thereby influencing the therapeutic index, off-tumour toxicity, and by-stander activity. Mechanistic insights increasingly show that linker–payload properties govern catabolite permeability and intratumoral distribution, particularly in antigen-heterogeneous settings. Current developments include enzyme-cleavable and tumour-selective linkers, polarity-modulating masking strategies, alternative self-immolative spacers, and dual-trigger systems designed to enhance selectivity and decouple efficacy from toxicity. In parallel, linker behaviour intersects with broader mechanisms of tumour resistance. This review focuses on understanding these processes, which are essential for designing the next generation of linkers capable of improving stability, safety, and long-term therapeutic effectiveness across diverse tumour contexts.
Sara N. Albino, Margarida M. Domingos, T. Pacheco et al.· Pharmaceutics· 0 citations
Piscidins are cationic α-helical antimicrobial peptides (AMPs) that constitute a key component of the innate immune defense of teleost fish, yet the relationship between their genomic organization, structural properties, and functional specialization remains incompletely understood. In this study, six piscidin peptides from Epinephelus akaara, Seriola dumerili, Thunnus maccoyii, Argyrosomus regius, Dicentrarchus labrax, and Epinephelus coioides were characterized through an integrated sequence-to-function approach combining comparative genomics, structural modeling, physicochemical analysis, and in vitro validation, with the aim of identifying candidates with potential for biomedical and biotechnological applications. All genes studied exhibited the conserved four-exon, three-intron architecture characteristic of teleost piscidins. Structural modeling and circular dichroism confirmed α-helical conformations under membrane-mimetic conditions, despite measurable differences in hydrophobicity, charge distribution, and predicted membrane insertion parameters. Antimicrobial assays revealed distinct functional profiles: Sd_FI25 and Epinecidin_1 displayed broad antibacterial activity against Gram-positive and Gram-negative pathogens, whereas Dl_FI22 showed selective activity with reduced temporal persistence associated with lower peptide stability. Ea_FF25 exhibited comparatively weak antibacterial potency. Antibiofilm activity varied among peptides and did not uniformly parallel planktonic MIC values. Computational predictions further suggested antiviral and antitumoral potential for several sequences, extending their prospective relevance beyond classical antibacterial roles. Conserved genomic architecture and α-helical structure coexist with pronounced functional diversification among teleost piscidins. These findings demonstrate that integrating structural prediction with experimental validation is an effective strategy for identifying fish-derived innate immune peptides as candidates for biomedical applications.
Patricia Asensio-Calavia, Sergio González-Acosta, M. Cavaco et al.· Fish and Shellfish Immunolog...· 0 citations