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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.
Highlights
Anthrax is a lethal disease caused by the spore-forming, Gram-positive bacteriumBacillus anthracis that can infect humans [1]
We previously demonstrated that antibodies of macaque origin are closed to human antibodies: the overall identity of the macaque variable heavy (VH) and variable light (VL) domain sequences with their most similar, human, germline gene counterpart is 78.5%, so they are predicted to be well-tolerated [14]
All purified antibody fragments were tested in ELISA and in surface plasmon resonance (SPR, Biacore® technology, Uppsala, Sweden) to determine their reactivity/affinity. single chain Fragment variable (scFv)/Fragment antigen binding (Fab) with affinity better than 10 nM for the target of interest were characterized in relevant in-vitro or ex-vivo neutralising assay
Summary
Anthrax is a lethal disease caused by the spore-forming, Gram-positive bacteriumBacillus anthracis that can infect humans [1]. Four forms of anthrax have been described so far: cutaneous, intestinal, inhalation, and injection anthrax. Each of these are lethal for humans in absence of treatment. Anthrax toxins and the antiphagocytic polyglutamic capsule are the two major virulence factors of B. anthracis These virulence factors are encoded by genes located in the plasmids PXO1 and PXO2, respectively. The Edema Toxin (ET) is composed of the PA and the Edema Factor (EF). Both toxins penetrate into the cell by endocytosis. The increase of cAMP results in the deregulation of water homeostasis (inducing an edema) and imbalance the intracellular signalling pathways and impairs de macrophage function, allowing the bacteria to further evade the immune system
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