Antitoxin Antibodies Development for Superbugs

The trend towards the development and spread of multi-drug resistant strains is of concern. Coupled with the lack of new antibiotics with novel mechanisms of action in the development pipeline, we need to develop non-antimicrobial approaches to fight superbugs. Monoclonal antibody-based approaches may provide a viable alternative for the treatment of certain multi-drug resistant bacterial infections. Antibody therapies against infections have focused on toxin neutralization, and several currently licensed therapies against bacteria target bacterial exotoxins.

Fig. 1 Antibodies neutralize the activity of pathogenic toxins to produce therapeutic effects. (McConnell M J, 2019)

Antitoxin monoclonal antibody therapies inhibit the virulence of drug-resistant bacteria to limit their invasion and damage to the host, while not creating selective pressure on the bacteria to develop new drug resistance. Ace Therapeutics provides services for the development of antitoxin monoclonal antibody-based superbug therapies, and attempts to design and generate monoclonal antibodies against toxins from drug-resistant bacteria such as Staphylococcus aureus, Streptococcus pyogenes, Clostridium spp. and Escherichia coli.

Our Antitoxin Antibodies Development Services

We typically employ histological techniques to identify antigens for potential use in monoclonal antibody development and to evaluate antibody candidates in preclinical studies. In summary, we are committed to achieving promising antibody drugs in the development of monoclonal antibodies for multi-drug resistant infections.

• Identification of target bacterial pathogens. We need to identify the secreted toxins that play a major role in the pathogenesis of the target bacterial pathogens. This means that bacterial infection disease is mainly mediated by the action of strong toxins.
• Epitope discovery. We neutralize toxins by designing antibodies to bind to highly conserved epitopes on toxin subunits. Therefore, we need to expose the toxin epitope to target for blockade.
• Design of antitoxin mAbs using functional information. We provide valuable functional information on the involved virulence of the mAb epitopes carrying the candidate. Such relevant information will be a promising starting point for antigen selection and prioritization to block the virulence properties of drug-resistant bacteria in a knowledge-based and precise manner. Note that we design monoclonal antibodies whose neutralizing effect on toxins is similar to blocking virulence but not viability of the pathogen.
• Optimization of antitoxin monoclonal antibodies. Antitoxin monoclonal antibodies do not possess antibacterial activity. Therefore, we can overcome the limitations by designing agents that incorporate direct antibacterial activity or by designing bispecific antibodies.

Epitope Standards

The development of monoclonal antibodies requires the targeting of validated epitopes. In this regard, we provide criteria for the selection of bacterial epitopes as ideal targets.

• High conservation between circulating strains.
• Expression during bacterial infection and/or colonization.
• Surface exposure to allow antibody binding.
• Different antigenicity compared to normal human epitopes to prevent cross-reactivity.

Key Development Directions

Several antitoxin monoclonal antibody-based therapies are already in development for the treatment of multi-drug resistant infections. We offer drug development and preclinical phase studies for some of the most worrisome antibiotic-resistant infections caused by multi-drug resistant gram-negative microorganisms.

• P. aeruginosa. Possible targets: protein subunit of the injectisome apparatus of the P. aeruginosa type III secretion system.
• Staphylococcus aureus. Possible targets: alpha-hemolysin, Staphylococcal enterotoxin.
• Klebsiella pneumoniae. Possible targets: endotoxin.

Contact us if you are interested in this area of research.

References

1. McConnell M J. Where are we with monoclonal antibodies for multidrug-resistant infections?. Drug Discovery Today, 2019, 24(5): 1132-1138.
2. Wang H, et al. Anti-bacterial monoclonal antibodies: next generation therapy against superbugs. Appl Microbiol Biotechnol, 2022, 106, 3957–3972.