Pulmonary delivery of anti-ricin antibody: From the bench to the clinic.

Ricin is a potent toxin, with a strong potential to be used as a biologicalweapon due to itsworldwide availability, ease of production in large quantities, and thermal stability. Inhalation of ricin is likely to be the intended route for acts of bioterrorism, because ricin is easily dispersed as an aerosol. Inhalation of ricin is the most lethal route of exposure, causing diffuse pulmonary edema and an increase of air-blood barrier permeability, leading to alveolar flooding and ultimately to death within a few days. Several approaches have been proposed to treat pulmonary ricin poisoning. These include prophylactic immunization with vaccines and post-exposure treatment with therapeutic antibodies, but none of these approaches are currently approved [1]. Post-exposure administration of neutralizing anti-ricin monoclonal antibodies (mAbs), delivered locally into the lungs, was effective in animals [1]. The intravenous route does not deliver a sufficient amount of mAbs to the respiratory tract. Although rapid diagnosis of ricin poisoning is currently available, optimization of inhalation to efficiently and rapidly deliver active mAbs directly into the lung has not been developed. The paper in this issue by Dr. Nathalie Heuzé-Vourc’h, her team and an international public-private consortium describes the development of a unique drug delivery system delivering a therapeutic monoclonal antibody (IgG 43RCA-G1) deep into the lungs to treat pulmonary ricin intoxication [2]. After developing a high-affinity neutralizing anti-ricin scFv antibody, the Heuzé-Vourc’h group modified it as a full length IgG close to human IgG to optimize for use in humans. Then, they tested its efficacy in vivo, in amurine lung challengemodel of ricin intoxication [3] and determined the therapeutic window using local delivery. They showed that IgG 43RCA-G1 rescued 100% of the mice for up to six hours after intoxication following direct delivery to the lungs, which is sufficient for intoxicated individuals to seek treatment and receive the antibody. The next step consisted of developing a drug delivery system to deliver IgG 43RCA-G1 by inhalation in humans. Successful inhalation depends on the performance of the device to efficiently deliver the drug to the target site, here the alveoli. The Heuzé-Vourc’h group was able to reduce the aerosol particle size and maximize delivery deep into the lung. It was necessary, however, to stabilize IgG 43RCA-G1 during the mesh nebulization and to facilitate its delivery under operational conditions. Thus, the Heuzé-Vourc’h group developed a dry-powder formulation of IgG 43RCA-G1 that would be reconstituted prior to nebulization in an adapted solution containing surfactants to avoidmAb aggregation. The aerosol characteristics and drug deposition of the drug