Bioinspired detoxification of blood: The efficient removal of anthrax toxin protective antigen using an extracorporeal macroporous adsorbent device

Ganesh Ingavle,Nathan Davies,Susan Sandeman,Les Baillie,Nigel Beaton,Sergey Mikhalovsky,Yishan Zheng

doi:10.1038/s41598-018-25678-0

Ganesh Ingavle, Nathan Davies + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-25678-0

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Abstract

Whilst various remedial human monoclonal antibodies have been developed to treat the potentially life-threatening systemic complications associated with anthrax infection, an optimal and universally effective administration route has yet to be established. In the later stages of infection when antibody administration by injection is more likely to fail one possible route to improve outcome is via the use of an antibody-bound, adsorbent haemoperfusion device. We report here the development of an adsorbent macroporous polymer column containing immobilised B. anthracis exotoxin-specific antibodies, PANG (a non-glycosylated, version of a plant-produced human monoclonal antibody) and Valortim (a fully human monoclonal N-linked glycosylated antibody), for removal of anthrax protective antigen (PA) from freshly frozen human plasma and human whole blood. In addition, we have demonstrated that continuous extracorporeal blood recirculation through a Valortim-bound haemoperfusion column significantly reduced the blood plasma concentration of anthrax PA over 2 hours using an in vivo PA rat infusion model. This work provides proof-of-concept evidence to support the development of such alternative detoxification platforms.

Highlights

Whilst various remedial human monoclonal antibodies have been developed to treat the potentially life-threatening systemic complications associated with anthrax infection, an optimal and universally effective administration route has yet to be established
Raxibacumab which has been approved by the FDA for the treatment of inhalational anthrax using the Animal Rule (US Food and Drug Administration 2012) increases survival in animal models when given pre-exposure[21] and has demonstrated a survival benefit for exposed rabbits when administered in combination with antibiotics[22]
We demonstrated that protein-A bound poly(acrylamide-co-allyl glycidyl ether) (AAm-AGE) cryogels had the physical properties and capacity to bind antibody for the removal of anthrax toxin protective antigen (PA) from phosphate buffered saline (PBS)[36]

Summary

Introduction

Whilst various remedial human monoclonal antibodies have been developed to treat the potentially life-threatening systemic complications associated with anthrax infection, an optimal and universally effective administration route has yet to be established. Extensive research has been undertaken to develop therapeutic antibodies which target anthrax toxin components and can provide protection when given alone or in combination with antibiotic treatment[13,14,15,16]. Several recombinant monoclonal antibodies (mAbs) such as PANG17, Valortim[18,19], and Raxibacumab[20] have been developed which bind to PA and have been shown to protect infected animals. They act by inhibiting different stages of the intoxication process, including the inhibition of PA-receptor binding, proteolytic cleavage, oligomerisation, internalisation, and EF/LF binding. Raxibacumab which has been approved by the FDA for the treatment of inhalational anthrax using the Animal Rule (US Food and Drug Administration 2012) increases survival in animal models when given pre-exposure[21] and has demonstrated a survival benefit for exposed rabbits when administered in combination with antibiotics[22]

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