Antibody radionuclide conjugates are an emerging modality for targeted imaging and potent therapy of disseminated disease. Coupling of radionuclides to monoclonal antibodies (mAbs) is typically achieved by applying non-site-specific labelling techniques. With the ambition of reducing variability, increasing labelling efficacy and stability, several site-specific conjugation strategies have been developed in recent years for toxin- and fluorophore-mAb conjugates. In this study, we studied two site-specific labelling strategies for the conjugation of the macrocyclic chelating agent, DOTA, to the anti-Leucine Rich Repeat Containing 15 (LRRC15) mAb DUNP19. Specifically, one approach utilized a DOTA-bearing peptide (FcIII) with a strong affinity for the fragment crystallizable (Fc) domain of the human IgG of DUNP19 (DUNP19-FcIII-DOTA), while the other leveraged a chemo-enzymatic technique to substitute the N-linked bi-antennary oligosaccharides in the human IgG Fc domain with DOTA (DUNP19-gly-DOTA). To assess if these methods impact the antibody's binding properties and targeting efficacy, comparative in vitro and in vivo studies of the generated DUNP19-conjugates were performed. While the LRRC15 binding of both radioimmunoconjugates remained intact, the conjugation methods had different impacts on their abilities to interact with FcRn and FcγRs. In vitro assessments of DUNP19-FcIII-DOTA and DUNP19-gly-DOTA demonstrated markedly decreased affinity for FcRn and FcγRIIIa (CD16), respectively. DUNP19-FcIII-DOTA demonstrated increased blood and tissue kinetics in vivo, confirming loss of FcRn binding. While the ablated FcγR interaction of DUNP19-gly-DOTA had no immediate impact on in vivo biodistribution, reduced immunotherapeutic effect can be expected in future studies as a result of reduced NK-cells interaction. In conclusion, our findings underscore the necessity for meticulous consideration and evaluation of mAb labelling strategies, extending beyond mere conjugation efficiency and radiolabeling yields. Notably, site-specific labelling methods were found to significantly influence the immunological impact of Fc interactions. Therefore, it is of paramount importance to consider the intended diagnostic or therapeutic application of the construct and to adopt conjugation strategies that ensure the preservation of critical pharmacological properties and functionality of the antibody in use.
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http://dx.doi.org/10.1016/j.ejmech.2024.116927 | DOI Listing |
3 Biotech
February 2025
Shree. S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva, Gujarat 384012 India.
This review assesses the antiviral capabilities of antimicrobial peptides (AMPs) against SARS-CoV-2 and other respiratory viruses, focussing on their therapeutic potential. AMPs, derived from natural sources, exhibit promising antiviral properties by disrupting viral membranes, inhibiting viral entry, and modulating host immune responses. Preclinical studies demonstrate that peptides such as defensins, cathelicidins, and lactoferrin can effectively reduce SARS-CoV-2 replication and inhibit viral spread.
View Article and Find Full Text PDFNarra J
December 2024
Research Center for Pre-Clinical and Clinical Research, National Research and Innovation Agency Republic of Indonesia, Jakarta, Indonesia.
The coronavirus disease 2019 (COVID-19) pandemic has encouraged global vaccine research, yet vaccine effectiveness in the elderly remains a concern due to immunosenescence. The aim of this study was to compare the cytokine response elicited by an inactivated virus-based COVID-19 vaccine between elderly and young adults, focusing on key cytokines involved in cellular and humoral immunity: tumor necrosis factor-alpha (TNF-α), interleukin (IL)-2, IL-6, IL-10, and interferon-gamma (IFN-γ). A cross-sectional study was conducted in the Jakarta-Bogor region of Indonesia from January 2023 to December 2023.
View Article and Find Full Text PDFOrg Biomol Chem
January 2025
Laboratory of Advanced Computation and Theory for Materials and Chemistry, Department of Chemistry, National Institute of Technology Warangal (NITW), Warangal, Telangana-506004, India.
The optical control of physiological processes with high precision using photoswitches is an emerging strategy for non-invasive diagnosis and therapies, providing innovative solutions to complex biomedical challenges. Light-responsive cyclic conjugated-dienes (cCDs) have long been recognized for their 4π-photocyclization; however, photoswitching behaviour in medium-sized cCDs has recently been reported, representing a pioneering discovery in the field. Reinforced by previous experimental evidence corroborating the Woodward-Hoffmann rules, this report provides insight into the origin of the exotic dual photoexcitation mechanism devised to achieve thermo-reversible photoswitching in large cCDs with cyclodeca-1,3-diene as a prototype.
View Article and Find Full Text PDFIn this Letter, we present a novel, to the best of our knowledge, approach for recovering objects directly from the Fraunhofer diffraction integral, where the diffraction field of an object is approximated by the Fourier transform of this object augmented by an additional phase factor. This phase factor at the observation plane is universal for the diffraction fields generated by objects located at the same plane and illuminated by the same monochromatic plane wave. It can be first extracted from dividing the Fraunhofer diffraction field by the Fourier transform of an object reference.
View Article and Find Full Text PDFNanomedicine (Lond)
January 2025
Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico (CRO) di Aviano IRCCS, Aviano, Italy.
Background: Drug delivery strategies using chitosan nanobubbles (CS-NBs) could be used to reduce drug side effects and improve outcomes in hepatocellular carcinoma (HCC) treatment. To enhance their action, a targeting agent, such as the humanized anti-GPC3 antibody GC33 (condrituzumab), could be attached to their surface. Here, we investigated the use of idarubicin-loaded CS-NBs for HCC treatment and a GC33-derived minibody (that we named 4A1) to enhance CS-NB delivery.
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