Biology subjects

de Vor, L.

Publications and source records attributed to de Vor, L..

3 recordsLinked to original sources

bioRxiv2026

C1q-mediated steric hindrance limits FcγR contribution to antibody-driven phagocytosis by human neutrophils

Phagocytosis and killing of bacteria by neutrophils is a key driver of human immunity against invading infections. IgG antibodies targeting the bacterial surface can potently enhance phagocytic uptake by engaging Fc gamma receptors (Fc{gamma}Rs) on the neutrophil membrane. In addition, IgG-mediated complement activation triggers surface deposition of complement opsonins that engage complement receptors (CRs) to further enhance target cell clearance. In this paper, we reveal that complement deposition prevents engagement of Fc{gamma}Rs to the Fc-domain of surface-bound IgG molecules. When complement is present, we observe that blockade of Fc{gamma}Rs does not influence phagocytosis of both Gram-positive and -negative bacteria (using Staphylococcus aureus and Klebsiella pneumoniae as model organisms). Complement-mediated hindrance of Fc{gamma}R engagement was observed in different model conditions, for example using either pre-existing polyclonal antibodies in human serum or recombinant monoclonal antibodies (mAbs) targeting different bacterial antigens. Using Fc engineering, we found that inhibition of Fc{gamma}R binding is dependent on the ability of IgGs to form IgG hexamers. Mechanistically, we show that complement proteins, in particular C1q, directly prevents the interaction between IgG-Fc and Fc{gamma}R by steric hindrance. Together, these insights help us define the respective roles of Fc{gamma}R and CR in neutrophil phagocytosis, while also providing important fundamental insights for therapeutic antibody development.

immunology↗

bioRxiv2023

Antibody-drug conjugates to treat bacterial biofilms

Implant-associated infections remain a grand unmet medical need because they involve biofilms that protect bacteria from the immune system and harbour antibiotic-tolerant persister cells. There is an urgent need for new biofilm-targeting therapies with antimicrobials, to treat these infections via a non-surgical way. In this work, we address this urgent medical need and engineer antibody-drug conjugates (ADC) that kill bacteria in suspension and in biofilms, in vitro and in vivo. The ADC contains an anti-neoplastic drug mitomycin C, which is also a potent antimicrobial against biofilms. While most ADCs are clinically validated as anti-cancer therapeutics where the drug is released after internalisation of the ADC in the target cell, the ADCs designed herein release the conjugated drug without cell entry. This is achieved with a novel mechanism of drug, which likely involves an interaction of ADC with thiols on the bacterial cell surface. ADC targeted towards bacteria were superior by the afforded antimicrobial effects compared to the non-specific counterpart, in suspension and within biofilms, in vitro and in vivo. An implant-associated murine osteomyelitis model was then used to demonstrate the ability of the antibody to reach the infection, and the superior antimicrobial efficacy compared to standard antibiotic treatment in vivo. Our results illustrate the development of ADCs into a new area of application with a significant translational potential.

microbiology↗

bioRxiv2021

Human monoclonal antibodies against Staphylococcus aureus surface antigens recognize in vitro biofilm and in vivo implant infections

Implant-associated Staphylococcus aureus infections are difficult to treat because of biofilm formation. Bacteria in a biofilm are often insensitive to antibiotics and host immunity. Monoclonal antibodies (mAbs) could provide an alternative approach to improve the diagnosis and/or treatment of biofilm-related infections. Here we show that mAbs targeting common surface components of S. aureus can recognize clinically relevant biofilm types. We identify two groups of antibodies: one group that uniquely binds S. aureus in biofilm state and one that recognizes S. aureus in both biofilm and planktonic state. In a mouse model, we show that mAb 4497 (recognizing wall teichoic acid (WTA)) specifically localizes to biofilm-infected implants. In conclusion, we demonstrate the capacity of several human mAbs to detect S. aureus biofilms in vitro and in vivo. This is an important first step to develop mAbs for imaging or treating S. aureus biofilms.

microbiology↗