PBEF Neutralizing Humanized Monoclonal Antibodies As Novel Therapeutic Approaches

DESCRIPTION (provided by applicant): Approximately 40-60% of patients admitted to intensive care units (ICU) require mechanical ventilation with acute lung injury (ALI) a common diagnosis which mandates intubation and placement on the ventilator. It is nowwell recognized that the development of VILI directly contributes to the unacceptably high mortality rate associated with ALI and despite the advances in ventilation strategies, VILI remains a major problem in ICU. VILI and ALI have common pathological features such as marked pulmonary capillary leakage, increased inflammatory cell influx and enhanced pro-inflammatory cytokine expression. Currently, the only remedial procedure in place is the use of low tidal volume ventilation, a practice not universallyembraced and insufficient to completely prevent VILI. Our previous work has identified PBEF, an inflammatory cytokine that accumulates in the lung fluid as one of the major underlying factors that mediated the damage seen in ALI/VILI. We also carried out proof-of-principle studies to demonstrate that neutralizing polyclonal antibodies against PBEF when administered intratracheally and also intravenously has significant reduction in mouse model of ALI/VILI. We therefore propose to generate humanized ant-PBEFmonoclonal antibodies (P- BEFizumab) that can be used as both prophylactic and therapeutic agents in patients with ALI/VILI. Once the credibility of these antibodies in treating patients with ALI/VILI is established, we believe that these antibodies willalso be useful in other lung disorders such as chronic obstructive pulmonary disorders and also in field situations such as the war front and biothreat situations like chemical or neurotoxin poisoning. PUBLIC HEALTH RELEVANCE: Acute lung injury is an extremely debilitating disease with a high mortality rate (35-40%) and with significant disparities as the elderly, African-descent and Latino patients are particularly susceptible to the ravages of this disease. Patients require mechanical ventilation to overcome severe hypoxia and respiratory failure and unfortunately, it can exacerbate the lung injury. We have shown PBEF as a major contributing factor, and propose to generate therapeutic humanized neutralizing anti-PBEF monoclonal antibodies to treat patients with acute lung injury.