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Novel antibody–antibiotic conjugate

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Brief:

• On Wednesday, Roche researchers published a paper in Nature online entitled, “Novel antibody–antibiotic conjugate eliminates intracellular S. aureus.“
• The major point of the paper is that by using antibiotic-armed antibodies, researchers were able to kill Staphylococcus aureus (S. aureus) in mice, despite the fact that potent antibiotics often fail to kill S. aureus.
• This method was used in the development of Roche/Genentech’s breast cancer drug Kadcyla

Insight:

Multi-drug resistant pathogens have become a serious challenge for infectious disease specialists and a major nosocomial killer. But now, researchers are finding new ways to target these hard-to-treat invaders.

By using targeting methods to seek out cancerous cells and kill them, oncologic researchers have been able to develop effective immunotherapeutic treatments for cancer, such as Kadcyla and Keytruda. Now researchers are turning their focus towards hard-to-treat bacterial infections.

Scientists’ success in killing S. aureus in host cells is significant because multidrug-resistant S. aureus (MRSA) is an extremely difficult-to-treat extracellular pathogen which colonizes host cells, thereby providing a protective reservoir against antibiotics.

This antibody–antibiotic conjugate technique looks promising, and could very well be one approach to finally combating the scourge of multi-drug resistant pathogens, including MRSA and others.

 

Novel antibody–antibiotic conjugate eliminates intracellular S. aureus

Sophie M. Lehar, Thomas Pillow, Min Xu, Leanna Staben, Kimberly K. Kajihara, Richard Vandlen, Laura DePalatis, Helga Raab, et al.
Nature (Nov 2015)     http://dx.doi.org:/10.1038/nature16057

Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S. aureus within host cells may provide a reservoir relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy. Here we confirm that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin, and we introduce a novel therapeutic that effectively kills intracellular S. aureus. This antibody–antibiotic conjugate consists of an anti-S. aureus antibody conjugated to a highly efficacious antibiotic that is activated only after it is released in the proteolytic environment of the phagolysosome. The antibody–antibiotic conjugate is superior to vancomycin for treatment of bacteraemia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections.

Figure 1: Intracellular MRSA are protected from vancomycin.

 

http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature16057-f1.jpg

 

Figure 3: AAC linker is cleaved after internalization of bacteria.

a, Live cell imaging monitoring cleavage of AAC linker in macrophages with FRET-based antibody conjugate (representative of three fields). TAMRA, tetramethylrhodamine. b, Mass spectrometric quantification of released antibiotic inside m…

http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature16057-f3.jpg

 

Figure 2: AAC design.

a, Model of AAC (not drawn to scale). b, Mechanism of AAC action. c, Binding of Alexa-488 anti-β-GlcNAC WTA monoclonal antibody (mAb) or anti-α-GlcNAC WTA monoclonal antibody, or isotype control antibody, anti-cytomegalovirus glycoprote…

http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature16057-f2.jpg

 

Figure 4: AAC is a more effective treatment than vancomycin after intravenous infection.

a, Wild-type (WT) mice (n = 8 per group) were treated with 50 mg kg⁻¹ of the indicated anti-MRSA antibodies 1 h before MRSA infection or twice daily with 110 mg kg⁻¹ vancomycin (Vanco). b, Treatment of wild-type mice (n = 5 per group) w…

http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature16057-f4.jpg