Neutralization of Pathogenic Fungi with Small‐Molecule Immunotherapeutics

Abstract

Systemic fungal infections represent an important public health concern, and new antifungal agents are highly desirable. Herein, we describe the design, synthesis, and biological evaluation of a novel class of antifungal compounds called antibody-recruiting molecules targeting fungi (ARM-Fs). Our approach relies on the use of non-peptidic small molecules, which selectively bind fungal cells and recruit endogenous antibodies to their surfaces, resulting in immune-mediated clearance. Using the opportunistic fungal pathogen Candida albicans as a model, we identified a highly specific bifunctional molecule able to mediate the engulfment and phagocytosis of C. albicans cells by human immune cells in biologically relevant functional assays. This work represents a novel therapeutic approach to treating fungal illness with significant potential to complement and/or combine with existing treatment strategies.

Universal endogenous antibody recruiting nanobodies capable of triggering immune effectors for targeted cancer immunotherapy

“…16,17 Many rationally designed ARMs, where preferred haptens that could be recognized by natural occurring endogenous antibodies, such as dinitrophenyl (DNP), galactose-α-1,3-galactose (αGal) and rhamnose (Rha), as an antibody-binding component, have been successfully achieved in cancer, [18][19][20][21][22] virus, 23, 24 bacterial 25,26 and others. 27 For example, we and others demonstrated that nanobody-DNP conjugates could form an in situ immune-complex with specific endogenous anti-DNP antibody existing in human serum and subsequently provoke potent ADCC and CDC cytotoxicity to target destructing cancer cells in vitro and exhibit in vivo antitumor activity in mouse xenograft models. 28,29 Notably, it is observed that the pharmacokinetic profile of nanobody-DNP conjugates was improved more than 20-fold in the presence of anti-DNP antibodies.…”

Multifunctional Glycoconjugates for Recruiting Natural Antibodies against Cancer Cells

“…[3,4] More recently,s everal groups have demonstrated that fully synthetic bifunctional molecules, named antibody recruiting molecules (ARMs), have the ability to redirect naturala ntibodies (Abs) against cancer cells to promote immune-mediated cytotoxicity. [5,6] Also used successfully against pathogens, [7][8][9][10] this concept is based on the covalent association of two distinct recognitiond omains, one for the antibodies present in humans and one for a cancer-specific biomarker,t hus enabling simultaneous binding of both Abs and cancer cells. For example, Kiessling and coworkers [11] described an ARM containingaRGD peptidomimetic as ligand for a v b 3 integrins and the a-Gal trisaccharide as specific epitope for al arge class of Abs present in the bloodstream of humans.T his molecule was able to inhibiti ntegrinmediated cell adhesion by creatingm ultivalent contactsa tt he cell surface and to recruit natural Abs from humans erum to mediate cytotoxicity against tumors.…”

A universal dual mechanism immunotherapy for the treatment of influenza virus infections

“…Hapten-targeted immunotherapies have also been explored for suppression of activated macrophages in murine models of inflammatory and autoimmune diseases 36,37 , with animal data again demonstrating impressive efficacy in all cases. More recently, related ligand-targeted hapten therapies have been developed to kill HIV-, bacteria-and fungus-infected cells, with analogous promising data again reported in all cases 18,43,44 . Taken together, these congruent data from multiple labs suggest that decoration of a pathogenic cell with a strongly immunogenic hapten can mediate eradication of the pathogenic cell in a variety of diseases.…”