PHARMACOKINETIC, PHARMACODYNAMIC, SAFETY AND TOXICOLOGICAL COMPARABILITY STUDY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this study is to evaluate the in vivo comparability of two monoclonal antibody (MAB) variants, TRX1 Leucine and TRX1 Proline. TRX1 Leucine and TRX1 Proline are identical except for one amino acid substitution in the Fc region of the antibody. Both MABs bind to the CD4 molecule found on white blood cells (lymphocytes) and are being evaluated as a potential treatment of autoimmune diseases (Chronic cutaneous lupus erythematosus), organ transplantation (kidney) and the extension of the effective use of currently available therapeutic agents (Factor VIII). In these conditions, the human body is rejecting its own protein (causing tissue damage) or a given treatment (rendering it inactive). TRX1 Leucine and TRX1 Proline are both believed to prevent or delay this response and therefore may have an enormous benefit to patients with these diseases or medical needs. Extensive investigation into safety and efficacy has occurred with TRX1 Leucine in baboons at SFBR. TRX1 Leucine single dose, multiple dose and dose ranging studies have been completed in baboons with no MAB related adverse events. TRX1 Proline has been selected for continued clinical development as it is more representative of a naturally occurring antibody and is believed to elicit less of an immune response in vivo. A successful comparison of these two MABs may alleviate the need to repeat an extensive preclinical program in baboons to assess many biological parameters already investigated with regards to TRX1 Leucine. In addition to limiting the use of baboons by streamlining the transition from TRX1 Leucine to TRX1 Proline in the clinic, this study may enable the sponsor to accelerate the pace of moving this beneficial treatment to the populations in need of medical assistance. The animals will be sedated and given seven 1 hour intravenous infusions of either TRX1 Leucine, TRX1 Proline, or saline every other day over a two-week period. Blood samples will be collected at various time points before and after infusions in order to evaluate a number of parameters including drug concentrations, immune response, serum chemistries, cell counts and cell typing. At the end of the seven infusions, 10 treated animals will be sacrificed and a complete necropsy performed. Tissues will be collected to examine possible effects on specific tissues due to drug administration. Prior to sacrifice, four animals, two treated with TRX1 Proline and two treated with saline, will be monitored during a six week recovery phase to assess any prolonged effect of MAB treatment.