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.
Highlights
IntroductionIt has been suggested that broad spectrum antimicrobial activity contributes to the widespread development of resistant strains, and specific mechanisms of resistance can either exist before, or emerge rapidly after, the clinical launch of new antibiotics [7]
The clinical application of antibodies for the treatment of infectious diseases was first introduced in the form of serum therapy in early 1890s by Emil von Behring and ShibasaburoKitasato [1]
Antibacterial monoclonal antibody (mAb) that act through the mechanism of neutralization are typically directed against exotoxins. mAb binding to soluble exotoxins leads to the formation of antibody-toxin complexes, which are primarily cleared by the reticuloendothelial system
Summary
It has been suggested that broad spectrum antimicrobial activity contributes to the widespread development of resistant strains, and specific mechanisms of resistance can either exist before, or emerge rapidly after, the clinical launch of new antibiotics [7]. There are only three mAbs approved by the FDA for use in the treatment of bacterial infections (Table 1). All three mAbs are indicated as adjuvant therapies to antibiotics and do not have bactericidal activity They are directed against bacterial exotoxins and protect host cells from toxin-mediated cytotoxicity through neutralization of exotoxin activities. Five of the nine mAb products in clinical testing bind to the bacterial cell surface and have shown bactericidal activity in preclinical studies (DSTA4637S, 514G3, MEDI3902, Aerumab, and Aerucin); the other four target exotoxins and protect against infections via toxin neutralization (MEDI4893, ASN100, Salvecin, and Shigamab). The PK/PD characteristics of FDA-approved antibacterial mAbs and those in clinical trial are summarized
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