This research plan relates to the preclinical development of antibodies capable of neutralizing staphylococcal enterotoxin B (SEB) in vivo. The ultimate objective of this proposal is to prepare for submission of an IND to the FDA by the year 2010 for the clinical development of Human Anti-SEB MAbs (HASMs). Morphotek and USAMRIID have been collaborating under a Cooperative Research and Development Agreement to generate innovative research that will advance the development of therapeutics specific for SEB, as well as other biowarfare toxins. Morphotek has identified at least two HASMs that can block SEB activity in vivo.
The aims of this proposal address all the requirements for an IND submission including but not limited to: justification and rationale of the proposed therapeutic approach;efficacy in animal models;toxicology and safety parameters of our antibodies(s);chemistry, manufacturing and controls (CMC) section;design of clinical protocol. This proposal is responding to a Request for Application (RFA) entitled """"""""Cooperative Research Partnerships into Therapeutics and Diagnostics for Biodefense Toxins"""""""", whereby SEB is one of the biodefense toxins included in this RFA. There is considerable need to develop vaccines and therapeutic strategies capable of preventing or reverse SEB toxicity, and with regard to significance, this application lays out what we believe is a well designed, structured plan to advance our HASMs from their current preclinical stage to clinical development in 3 years. In this work plan, one objective is to further improve the potency of the current HASMs by increasing their affinities using Morphotek's antibody optimization technology named morphogenics, and to find HASMs combinations and ratios that would allow lowering the HASMs dose (e.g. <7 mg/kg in man) or increase their neutralization power (e.g. block >1,000 human LD50). One major objective is to demonstrate survival of rhesus monkeys challenged with aerosol SEB and treated 4 hours later with HASMs. To study the safety of HASMs, toxicology studies will be conducted in rats and cynomolgus, and potential HASMs crossreactivity to normal human tissues will be assessed using immunohistochemistry under GLP. The process for the manufacturing of HASMs will be optimized to achieve >0.5 gram/L titers and GMP material will be generated to support toxicology studies.
