Optimized lactoferrin for treatment of intracerebral hemorrhage

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 DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is a major public health problem with the highest mortality rate of all stroke subtypes. ICH is one of the leading causes of long-term disability. Since there are no available FDA- approved therapies for ICH, it is of vast importance to search for new approaches in treatment for this devastating medical condition. Lactoferrin (LTF) is a well-known endogenous glycoprotein with anti-microbial and immunoregulatory functions, in part through its effective sequestration of free iron. In our ongoing research, using different in vitro cell-culture systems (to model ICH pathogenesis) and clinically relevant rodent models of ICH, we discovered that lactoferrin (LTF) has unique pleiotropic activities. This makes this endogenous protein highly attractive as a therapeutic candidate for the treatment of ICH. Because LTF is rapidly removed from the circulation (T1/2 ~45 min), we developed a novel fusion protein based on recombinant human lactoferrin (rhLTF) and Fc domain of IgG for neonatal Fc receptor (PRC14). This novel molecule has indeed a significantly extended half- life (5.8 fold) over native LTF. We successfully accomplished the objectives of Phase I by defining the optimal therapeutic dose of PRC14 and showing extraordinary therapeutic window (24h) in a mouse model of ICH. The primary objective of this Phase II is: (i) to validate the safety of PRC14 as a potential therapeutic expressed in stable CHO (DG44) cells according to GMP standards (Aim 1), and (ii) to further characterize the therapeutic utility of PRC14 in treatment for ICH, using animal models that simulate clinical risk factors and known determinants of poor outcome after ICH (Aim 2). Further commercialization of PRC14 will require a robust, scalable procedure where the final material retains activity and meets compliance requirements for pre-clinical safety and toxicology in animals. We will accomplish this goal with PRC14 being produced in stable CHO cells under GMP protocols and tested according to GLP protocols for: (i) pharmacokinetics; (ii) single dose safety studies (toxicity); and (iii) repeat dose, 7-day safety studies (toxicity) in rats. The PRC14 obtained from scale-up production (25g) will be used to assess early edema and long-term neurological deficit: (i) in aged female and male mice, (ii) in spontaneously hypertensive rats (SHR), and (iii) in a pig model allowing for larger hematoma size. This design should provide the strong foundation for future clinical studies.