Decoding the Nectin Interactome: Implications for Brain Development, Plasticity, and Neurological DisordersYadav, Srinivasan, Sharma
et alACS Chem Neurosci (2025) 16 (6), 1000-1020
Abstract: The nectin family of cell adhesion molecules (CAMs) comprising nectins and nectin-like molecules has emerged as a key regulator of various pivotal neural processes, including neuronal development, migration, synapse formation, and plasticity. Nectins engage in homophilic and heterophilic interactions to mediate cell-cell adhesion, contributing to the establishment and maintenance of neural circuits. Their extracellular domains facilitate trans-synaptic interactions, while intracellular domains participate in signaling cascades influencing cytoskeletal dynamics and synaptic function. The exhibition of distinct localization patterns in neurons, astrocytes, and the blood-brain barrier underscores their diverse roles in the brain. The dysregulation of nectins has been implicated in several neurological disorders, such as neurodevelopmental disorders, depression, schizophrenia, and Alzheimer's disease. This review examines the structural and functional characteristics of nectins and their distribution and molecular mechanisms governing neural connectivity and cognition. It further discusses experimental studies unraveling nectin-mediated pathophysiology and potential therapeutic interventions targeting nectin-related pathways. Collectively, this comprehensive analysis highlights the significance of nectins in brain development, function, and disorders, paving the way for future research directions and clinical implications.
A novel and promising therapeutic approach for treating pancreatic cancer: Nectin‑4‑targeted antibody‑drug conjugates alone or combined with autophagy inhibitorsFu, Wang, Yin
et alInt J Mol Med (2025) 55 (4)
Abstract: Antibody‑drug conjugates (ADCs) are rapidly advancing the treatment of solid tumors, and Nectin‑4‑targeted ADCs have been approved by the FDA to treat certain cancers. Although Nectin‑4 is overexpressed in the tissues of patients with pancreatic cancer, whether Nectin‑4‑targeted ADCs can effectively treat pancreatic cancer remains unclear. The present study evaluated the therapeutic effects and mechanisms of Nectin‑4‑targeted ADCs in pancreatic cancer. A Nectin‑4‑directed ADC was chosen, Nectin‑4‑MMAE, which triggered apoptosis and induced cell death in the Nectin‑4‑positive pancreatic cancer cell lines BxPC‑3 and YAPC. Nectin‑4‑MMAE also induced autophagy in BxPC‑3 and YAPC cells by inactivating the AKT/mTOR pathway. The entire autophagy process was observed by electron microscopy and laser confocal microscopy. The autophagy inhibitors LY294002 and chloroquine significantly increased the lethal effects of Nectin‑4‑MMAE on BxPC‑3 and YAPC cells by inducing apoptosis. In the xenograft tumor model, Nectin‑4‑MMAE alone elicited potent antitumor effects. When Nectin‑4‑MMAE was combined with autophagy inhibitors, the tumor burden of mice was decreased compared with treatment with either drug alone. The present study confirmed the potent therapeutic effects of Nectin‑4‑MMAE against pancreatic cancer, and its unique antitumor mechanism provides new approaches to treatment.
Targeting Herpes Simplex Virus Glycoprotein D with Bispecific Antibodies: Expanding Therapeutic Horizons by Searching for SynergyAtanasiu, Saw, Friedman
et alViruses (2025) 17 (2)
Abstract: Herpes simplex viruses (HSV-1 and HSV-2), which can be transmitted both orally and sexually, cause lifelong morbidity and in some cases, meningitis and encephalitis. While both the passive transfer of neutralizing antibodies and placental transfer of anti-HSV monoclonal antibodies (Mabs) have shown therapeutic promise in animal models, clinical trials have yet to identify approved immunotherapeutics for herpes infection. Here, we present strategies for the generation of recombinant bispecific antibodies (BsAbs) that target different domains of glycoprotein D (gD), crucial for HSV entry, that have the potential to outperform the effect of individual Mabs to curb herpes infection. Specifically, we selected three pairs of Mabs from our extensive panel for BsAb design and production based on their binding site and ability to block virus entry. Actual binding of BsAbs to gD and epitope availability on gD after BsAb binding were characterized using surface plasmon resonance (SPR) and inhibition by IgG Fab fragments generated from selected Mabs. While one BsAb exhibited an additive effect similar to that observed using a combination of the Mabs utilized for its generation, two showed antagonistic effects, suggesting that the simultaneous engagement of two epitopes or selective binding to one affected their activity against HSV. One BsAb (DL11/1D3) targeting the binding site for both nectin-1 and HVEM receptors demonstrated synergistic inhibitory activity against HSV, outperforming the effect of the individual antibodies. Recombinant DL11/1D3 antibody variants, in which the size of one or both paratopes was decreased to single chains (scFv-Fc), highlighted differences in potency depending on antibody size and format. We propose that BsAbs to individual glycoproteins offer a potential avenue for herpes therapeutics, but their design, mechanism of action, antibody format, and epitope engagement require careful consideration of structure for optimal efficacy.
Early-life stress of limited bedding/nesting material induced recognition memory loss and decreased hippocampal VGluT1 and nectin3 levels in aged male miceHe, Yu, Wang
et alPharmacol Biochem Behav (2025) 249, 173980
Abstract: Exposure to early-life stress has been found to lead to enduring psychiatric symptoms, including cognitive impairments that persist into adulthood and even old age. In this study, we investigated the behavioral effects and molecular changes of a well-established animal model of early-life stress, the limited bedding and nesting (LBN) model, in aged male mice. After 16 months, stressed mice showed a marked impairment in novel and spatial object recognition tasks, but not in temporal order memory or spatial working memory in the Y-maze spontaneous alternation task. These cognitive deficits were accompanied by a reduction in VGluT1 expression and a lower VGluT1/VGAT ratio in the CA1 region of the hippocampus, as well as reduced nectin3 expression in the mouse hippocampus. No significant molecular alterations were observed in the medial prefrontal cortex. These data support the notion that early-life stress leads to cognitive impairments in aged male mice, and these effects may be associated with a dysregulated excitatory/inhibitory balance and reduced nectin3 levels in the hippocampus.Copyright © 2025 Elsevier Inc. All rights reserved.
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