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

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.     

Smallpox models as policy tools

Mathematical models can help prepare for and respond to bioterrorism attacks, provided that their strengths and weaknesses are clearly understood. A series of initiatives within the Department of Health and Human Services brought modelers together with biologists and epidemiologists who specialize in smallpox and experts in bioterrorism response and health policy and has led to the parallel development of models with different technical approaches but standardized scenarios, parameter ranges, and outcome measures. Cross-disciplinary interactions throughout the process supported the development of models focused on systematically comparing alternate intervention strategies, determining the most important issues in decision-making, and identifying gaps in current knowledge.     

CD28: Direct and Critical Receptor for Superantigen Toxins

Every adaptive immune response requires costimulation through the B7/CD28 axis, with CD28 on T-cells functioning as principal costimulatory receptor. Staphylococcal and streptococcal superantigen toxins hyperstimulate the T-cell-mediated immune response by orders of magnitude, inducing a lethal cytokine storm. We show that to elicit an inflammatory cytokine storm and lethality, superantigens must bind directly to CD28. Blocking access of the superantigen to its CD28 receptor with peptides mimicking the contact domains in either toxin or CD28 suffices to protect mice effectively from lethal shock. Our finding that CD28 is a direct receptor of superantigen toxins broadens the scope of microbial pathogen recognition mechanisms.     

Clinical and Pathological Findings Associated with Aerosol Exposure of Macaques to Ricin Toxin

Ricin is a potential bioweapon that could be used against civilian and military personnel. Aerosol exposure is the most likely route of contact to ricin toxin that will result in the most severe toxicity. Early recognition of ricin exposure is essential if specific antidotes are to be applied. Initial diagnosis will most likely be syndromic, i.e., fitting clinical and laboratory signs into a pattern which then will guide the choice of more specific diagnostic assays and therapeutic interventions. We have studied the pathology of ricin toxin in rhesus macaques exposed to lethal and sublethal ricin aerosols. Animals exposed to lethal ricin aerosols were followed clinically using telemetry, by clinical laboratory analyses and by post-mortem examination. Animals exposed to lethal aerosolized ricin developed fever associated with thermal instability, tachycardia, and dyspnea. In the peripheral blood a marked neutrophilia (without immature bands) developed at 24 h. This was accompanied by an increase in monocytes, but depletion of lymphocytes. Red cell indices indicated hemoconcentration, as did serum chemistries, with modest increases in sodium and blood urea nitrogen (BUN). Serum albumin was strikingly decreased. These observations are consistent with the pathological observations of fluid shifts to the lungs, in the form of hemorrhages, inflammatory exudates, and tissue edema. In macaques exposed to sublethal aerosols of ricin, late pathologic consequences included chronic pulmonary fibrosis, likely mediated by M2 macrophages. Early administration of supportive therapy, specific antidotes after exposure or vaccines prior to exposure have the potential to favorably alter this outcome.     

Reframing the ‘securitization of public health’: a critical race perspective on post-9/11 bioterrorism preparedness in the US

This paper builds on the work of critical health scholars and practitioners who have examined the ‘securitization’ of public health in the US during the post-9/11 period. Adopting a critical race perspective, I delve more deeply into the racialized dimensions of this securitization, analyzing how the emergence of a bioterror-framed view of disease has mobilized a disease-terror imaginary comprised of longstanding suspicion towards bodies of color coupled with more recent anti-Arab and anti-Muslim sentiment. I demonstrate that the incorporation of the central figure of this imaginary – the bioterrorist – into US public health discourse has reconfigured ideas about disease carriers as potentially violent and malicious, in turn reconfiguring approaches to disease control that rely on suspicion and securitized health surveillance. US public health adoption of this orientation towards disease control has, I argue, the potential to exacerbate targeting, stigma, and exclusionary practices towards individuals and populations deemed suspicious vis-à-vis this imaginary. My work, in examining the racial discourses of bioterror that shape ‘securitization’, aims to expand the analytical tools that US public health administrators and practitioners draw on to remain vigilant in ensuring that it serves all of its publics in an equitable manner.     

Role of the Mannose Receptor (CD206) in Innate Immunity to Ricin Toxin

The entry of ricin toxin into macrophages and certain other cell types in the spleen and liver results in toxin-induced inflammation, tissue damage and organ failure. It has been proposed that uptake of ricin into macrophages is facilitated by the mannose receptor (MR; CD206), a C-type lectin known to recognize the oligosaccharide side chains on ricin's A (RTA) and B (RTB) subunits. In this study, we confirmed that the MR does indeed promote ricin binding, uptake and killing of monocytes in vitro. To assess the role of MR in the pathogenesis of ricin in vivo, MR knockout (MR(-/-)) mice were challenged with the equivalent of 2.5× or 5× LD(50) of ricin by intraperitoneal injection. We found that MR(-/-) mice were significantly more susceptible to toxin-induced death than their age-matched, wild-type control counterparts. These data are consistent with a role for the MR in scavenging and degradation of ricin, not facilitating its uptake and toxicity in vivo.     

Synthesis and early development of hexadecyloxypropylcidofovir: an oral antipoxvirus nucleoside phosphonate

Hexadecyloxypropyl-cidofovir (HDP-CDV) is a novel ether lipid conjugate of (S)-1-(3-hydroxy-2-phosphonoylmethoxypropyl)-cytosine (CDV) which exhibits a remarkable increase in antiviral activity against orthopoxviruses compared with CDV. In contrast to CDV, HDP-CDV is orally active and lacks the nephrotoxicity of CDV itself. Increased oral bioavailability and increased cellular uptake is facilitated by the lipid portion of the molecule which is responsible for the improved activity profile. The lipid portion of HDP-CDV is cleaved in the cell, releasing CDV which is converted to CDV diphosphate, the active metabolite. HDP-CDV is a highly effective agent against a variety of orthopoxvirus infections in animal models of disease including vaccinia, cowpox, rabbitpox and ectromelia. Its activity was recently demonstrated in a case of human disseminated vaccinia infection after it was added to a multiple drug regimen. In addition to the activity against orthopoxviruses, HDP-CDV (CMX001) is active against all double stranded DNA viruses including CMV, HSV-1, HSV-2, EBV, adenovirus, BK virus, orf, JC, and papilloma viruses, and is under clinical evaluation as a treatment for human infections with these agents.     

美国生物防御战略计划分析

生物恐怖与新发、突发传染病应对是当今人类社会面临的重大安全问题.美国高度重视生物防御能力建设,发布了多项与生物防御相关的国家战略并开展了一系列的生物防御计划.本研究分析了美国《21世纪生物防御》、《应对生物威胁国家战略》等生物防御战略以及生物盾牌计划、生物监测计划等生物防御计划的特点及对我国的启示.美国生物防御战略引领其生物防御计划的实施,生物防御计划推动其生物防御能力的提升,同时其生物防御能力建设结合了自然发生传染病的应对.我国应建立明确的生物防御战略,有计划分阶段地实施生物防御计划,同时加强对自然发生新发、突发传染病的应对能力建设.