Antibody‐Drug Conjugates to Treat Bacterial Biofilms via Targeting and Extracellular Drug Release

Abstract

The treatment of implant‐associated bacterial infections and biofilms is an urgent medical need and a grand challenge because biofilms protect bacteria from the immune system and harbor antibiotic‐tolerant persister cells. This need is addressed herein through an engineering of antibody‐drug conjugates (ADCs) that contain an anti‐neoplastic drug mitomycin C, which is also a potent antimicrobial against biofilms. The ADCs designed herein release the conjugated drug without cell entry, via a novel mechanism of drug release which likely involves an interaction of ADC with the thiols on the bacterial cell surface. ADCs targeted toward bacteria are superior by the afforded antimicrobial effects compared to the non‐specific counterpart, in suspension and within biofilms, in vitro, and in an implant‐associated murine osteomyelitis model in vivo. The results are important in developing ADC for a new area of application with a significant translational potential, and in addressing an urgent medical need of designing a treatment of bacterial biofilms.

Monoclonal Antibodies as a Therapeutic Strategy against Multidrug-Resistant Bacterial Infections in a Post-COVID-19 Era

“…Antibody-drug conjugations, bispecific mAbs, IgYs, Nanobodies, and scFvs are novel types of mAbs that have gained significant attention in recent years (Table 2). Antibodydrug conjugation is a technique where drugs or toxins are covalently attached to the immunoglobulin [59]. Bispecific mAbs combine two distinct mAbs to simultaneously target two different proteins [60].…”

“…Each novel mAb type possesses unique characteristics and advantages. Antibody-drug conjugates can deliver drugs or toxins to specific sites, holding particular promise for killing cancer cells or microbes [59]. Bispecific mAbs can cause multiple physiological or anti-tumor responses by targeting two antigens or epitopes simultaneously [60].…”

A comprehensive overview on antibody-drug conjugates: from the conceptualization to cancer therapy

“…In recent years, research groups have investigated the use of ADCs in non-oncologic contexts, mainly focusing on the treatment of bacterial infections and autoimmune diseases. Tvilum et al achieved antimicrobial efficacy by developing an Antibody-Antibiotic Conjugate (AAC), an antibody directed against bacteria conjugated to the antimicrobial molecule mitomycin C, for the treatment of implant-associated biofilm infections caused by Staphylococcus aureus , the most common causative agent in prosthetic joint infections ( Tvilum et al, 2023 ). In another study, O-Leary et al proposed the development of an Antibody-Bactericide Conjugate (ABC), an antibody conjugated to an antimicrobial peptide that exerts its effect by binding to the cell surface of P. aeruginosa , providing another interesting example of ADC activity against bacterial infections ( O'Leary et al, 2023 ).…”

“…Beginning with the first ADC, which was approved by the Food and Drug Administration (FDA) in 2000 ( Norsworthy et al, 2018 ), and given the ever-evolving technology of mAbs, linkers, and payloads, by April 2023 13 different ADCs have been FDA-approved for clinical use for both solid and hematologic malignancies, setting the stage for a new era of targeted cancer therapy ( Dumontet et al, 2023 ). In addition, a few studies have already addressed the potential use of ADCs in non-oncologic context, including infections ( O’Leary et al, 2023 ; Tvilum et al, 2023 ) and auto-immune disorders ( Lee et al, 2017 ; Yasunaga et al, 2017 ), with promising results showing the possibility of expanding the use of ADCs in various diseases. In this review, we aim to summarize the current knowledge of ADCs and address some key points about their molecular properties, their interaction with tumor mass and TME, their clinical use, toxicities and combinate regimens in cancer treatment.…”