Abstract
Conventional bivalent IgG antibodies targeting a subgroup of receptors of the TNF superfamily (TNFSF) including fibroblast growth factor-inducible 14 (anti-Fn14) typically display no or only very limited agonistic activity on their own and can only trigger receptor signaling by crosslinking or when bound to Fcγ receptors (FcγR). Both result in proximity of multiple antibody-bound TNFRSF receptor (TNFR) molecules, which enables engagement of TNFR-associated signaling pathways. Here, we have linked anti-Fn14 antibodies to gold nanoparticles to mimic the “activating” effect of plasma membrane-presented FcγR-anchored anti-Fn14 antibodies. We functionalized gold nanoparticles with poly-ethylene glycol (PEG) linkers and then coupled antibodies to the PEG surface of the nanoparticles. We found that Fn14 binding of the anti-Fn14 antibodies PDL192 and 5B6 is preserved upon attachment to the nanoparticles. More importantly, the gold nanoparticle-presented anti-Fn14 antibody molecules displayed strong agonistic activity. Our results suggest that conjugation of monoclonal anti-TNFR antibodies to gold nanoparticles can be exploited to uncover their latent agonism, e.g., for immunotherapeutic applications.
Highlights
Accepted: 7 July 2021Cancer immunotherapy is a rapidly developing field with a high potential to provide a cure for difficult to treat cancers
Gold nanoparticles of diameter ca. 60 nm have been synthesized via sodium citrate reduction of gold chloride and functionalized with COOH-poly-ethylene glycol (PEG)-SH to stabilize the colloidal suspension of the gold nanoparticles
We have demonstrated that the carboxyl-modified gold nanoparticles can be coupled with antibodies of interest using the ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)/NHS coupling procedure
Summary
Accepted: 7 July 2021Cancer immunotherapy is a rapidly developing field with a high potential to provide a cure for difficult to treat cancers. Some of the most promising novel immunotherapeutic reagents under consideration target tumor necrosis factor (TNF) receptor superfamily (TNFRSF) receptors (TNFRs) in immune regulation and tumor surveillance [1]. It is noteworthy that many TNFRs, including the immunotherapeutic interesting immune stimulatory receptors CD40, 41BB, CD27, OX40, and TNFR2 and fibroblast growth factor inducible 14 (Fn14), are only robustly activated by their membrane-bound ligands but less or not in soluble form [2]. There are obstacles in the development of agonistic recombinant soluble TNFSF ligands, including limited agonism, stability, and pharmacokinetics [3,4,5]. Agonistic antibodies targeting TNFRs are considered as useful alternative reagents to activate TNFRs
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