Pharmacokinetic and Pharmacodynamic Considerations for the Use of Monoclonal Antibodies in the Treatment of Bacterial Infections

Abstract

Antibiotic-resistant bacterial pathogens are increasingly implicated in hospital-and community-acquired infections. Recent advances in monoclonal antibody (mAb) production and engineering have led to renewed interest in the development of antibody-based therapies for treatment of drug-resistant bacterial infections. Currently, there are three antibacterial mAb products approved by the Food and Drug Administration (FDA) and at least nine mAbs are in clinical trials. Antibacterial mAbs are typically developed to kill bacteria or to attenuate bacterial pathological activity through neutralization of bacterial toxins and virulence factors. Antibodies exhibit distinct pharmacological mechanisms from traditional antimicrobials and, hence, cross-resistance between small molecule antimicrobials and antibacterial mAbs is unlikely. Additionally, the long biological half-lives typically found for mAbs may allow convenient dosing and vaccine-like prophylaxis from infection. However, the high affinity of mAbs and the involvement of the host immune system in their pharmacological actions may lead to complex and nonlinear pharmacokinetics and pharmacodynamics. In this review, we summarize the pharmacokinetics and pharmacodynamics of the FDA-approved antibacterial mAbs and those are currently in clinical trials. Challenges in the development of antibacterial mAbs are also discussed.

Monoclonal antibodies as anti-infective products: a promising future?

“…As such, bispecific antibodies aim to ensure enhanced potency and breadth of protection [30e32]. Other developments include antigen-binding (Fab) fragments, single chain variable fragments (ScFv) and pairs linked in different ways, as to create formats combining optimal size, half-life, activity and safety [25,33], as well as novel delivery systems such as antibodyeantimicrobial conjugates and radioimmunoconjugates [34,35]. Effector functions can be modified: Fc domain changes may enhance the affinity to Fc receptors on phagocytic cells, NK cells and B cells, and hence enforce antibody-dependent killing, whilst mutations leading to increased binding affinity for neonatal Fc receptor (FcRn) contribute to an extended half-life of the antibody [25].…”

“…preventing cell entry or neutralizing toxins) or via indirect mechanisms (e.g. modulating inflammatory responses or promoting opsonic phagocytosis) [26,34,36].…”

“…To date, licensed antibacterial mAbs target exotoxins, with the antigeneantibody complexes primarily removed via the reticuloendothelial system [1,6,7,34]. Instead, mAbs may bind to structural cell surface components (proteins and exopolysaccharides), with subsequent direct bactericidal clearance or immune system dependent cytotoxicity (antibody or complement dependent) [34]. In this regard, the pharmacodynamic mode of action varies amongst the candidate products currently under development [34].…”

“…Notwithstanding previous disappointment in translational research [37], activities which target Staphylococcus aureus and Pseudomonas aeruginosa are the most developed so far (B. François et al, 'Safety and tolerability of a single administration of AR-301, a human monoclonal antibody, in patients with severe pneumonia caused by Staphylococcus aureus: first in man trial,' abstract 1992, paper presented at European Congress of Clinical Microbiology and Infectious Diseases 2017) [34,38].…”

Special Issue: Monoclonal Antibodies

“…Cho and colleagues [1] review the state of the art in the therapy of multiple myeloma where antibody-based immunotherapies are changing the current treatment paradigm, and Wang-Lin and Balthasar summarize pharmacokinetic and pharmacodynamic considerations that are important for the treatment of bacterial infections by monoclonal antibodies [2]. Finally, Fülöp and colleagues review the role of complement activation in infusion reactions associated with the application of monoclonal antibodies and the potential use of complement factor H for its prevention [3].…”