Antibodies against Anthrax Toxins: A Long Way from Benchlab to the Bedside

Abstract

Anthrax is an acute disease caused by the bacterium Bacillus anthracis, and is a potential biowarfare/bioterrorist agent. Its pulmonary form, caused by inhalation of the spores, is highly lethal and is mainly related to injury caused by the toxins secretion. Antibodies neutralizing the toxins of B. anthracis are regarded as promising therapeutic drugs, and two are already approved by the Federal Drug Administration. We developed a recombinant human-like humanized antibody, 35PA83 6.20, that binds the protective antigen and that neutralized anthrax toxins in-vivo in White New Zealand rabbits infected with the lethal 9602 strain by intranasal route. Considering these promising results, the preclinical and clinical phase one development was funded and a program was started. Unfortunately, after 5 years, the preclinical development was cancelled due to industrial and scientific issues. This shutdown underlined the difficulty particularly, but not only, for an academic laboratory to proceed to clinical development, despite the drug candidate being promising. Here, we review our strategy and some preliminary results, and we discuss the issues that led to the no-go decision of the pre-clinical development of 35PA83 6.20 mAb. Our review provides general information to the laboratories planning a (pre-)clinical development.

Anthrax revisited: how assessing the unpredictable can improve biosecurity

“…In 2009, the first monoclonal antibody targeting PA was finally authorized by the FDA ( Migone et al, 2015 ). Nowadays, three anthrax antitoxins have been approved by the FDA and stockpiled by the United States: two monoclonal antibodies (raxibacumab and obiltoxaximab “Anthim”), and the human polyclonal purified IgG from vaccinated humans (intravenous anthrax immune globulin AIG-IV, also referred as Anthrasil) ( Huang et al, 2015 ; Avril et al, 2022 ), regardless of uncertainties associated with the clinical effectiveness of antibodies. Hence, Anthim and Anthrasil can be administered solo or in combination with antibiotics for a more effective anthrax therapy.…”

“…Hence, Anthim and Anthrasil can be administered solo or in combination with antibiotics for a more effective anthrax therapy. According to the CDC, the administration of both antibiotics and antibodies is recommended, regardless of recent studies doubting the efficiency of antibodies ( Tournier et al, 2019 ; Avril et al, 2022 ).…”

Nanobody-mediated neutralization of candidalysin prevents epithelial damage and inflammatory responses that drive vulvovaginal candidiasis pathogenesis

“…To successfully implement this therapeutic strategy, future work should prioritize preparing a nanobody formulation that can be applied in vivo . Various considerations are needed to develop such a therapy including pharmocokinetic and stability studies ( 58 ). Nevertheless, by combining wet bench techniques with bioinformatic modeling, we were able to provide a pre-clinical proof of concept as basis for anti-candidalysin nanobody therapy.…”

A Historical Review of Military Medical Strategies for Fighting Infectious Diseases: From Battlefields to Global Health

“…In 2016, another monoclonal antibody, obiltoxaximab, was approved by FDA. Currently, further monoclonal antibodies are under study, based on the assumption that targeting different anthrax antigens may be more effective [ 542 ].…”