The impact of hematopoietic stem cell transplantation (HSCT), a potentially curative therapy for both malignant and benign lymphohematopoietic diseases, is limited by acute graft-versus-host disease (aGVHD). Both animal models and human studies indicate that an important trigger of aGVHD is lipopolysaccharide (LPS, or endotoxin) that is believed to enter the peripheral circulation as a consequence of intestinal damage due to myeloablative conditioning regimens. Our preliminary data demonstrate that myeloablative HSCT is associated with severely diminished plasma levels of bactericidal/permeability-increasing protein (BPI), a neutrophil- derived molecule with potent and specific LPS-neutralizing activity. Thus, patients undergoing myeloablative HSCT are endotoxemic at a time when an endogenous anti-endotoxin defense, BPI, is severely deficient. We hypothesize that BPI deficiency compromises the ability of individuals undergoing HSCT to neutralize LPS, increasing risk for LPS-induced TNF-1 production and other downstream events that result in an increased risk for aGVHD and regimen-related toxicity. The premise of the proposed clinical trial is that early infusion of a bioactive recombinant N-terminal BPI fragment (rBPI21, Opebacan; XOMA U.S. LLC) with potent endotoxin- neutralizing activity and demonstrated safety in human clinical trials, will replace the deficient BPI thereby rapidly shielding patients from endotoxin-induced inflammatory responses.
In Specific Aim 1, we will determine the tolerability and pharmacokinetics of rBPI21 in BPI-deficient HSCT recipients in order to establish an understanding of the dose and schedule that will effectively block LPS mediated toxicity. The effects of rBPI21 infusion on the endotoxin-modulating activity of plasma will be investigated in Specific Aim 2.
Specific Aim 3 will focus on determining the effect of rBPI21 infusion on the functional expression of the endotoxin receptor composed of MD-2, TLR4, and mCD14. This clinical experiment and its biological endpoints will establish whether rBPI21 modulates endotoxin mediated pathophysiology in HSCT patients. Moreover, the data derived from the proposed experiments will provide the necessary clinical and scientific information to design pivotal studies that will examine the potential of this novel and uniquely non-immunosuppressive approach to ameliorate one of the major causes of HSCT morbidity and mortality.
The success of hematopoietic stem cell transplantation, a potentially curative therapy for many diseases, is limited by acute graft-versus-host disease (aGVHD). Our preliminary data demonstrate that myeloablative transplant is associated with severely diminished plasma levels of the endotoxin-neutralizing protein (BPI), thereby increasing risk for endotoxin-induced events that result in aGVHD and other toxicities. Here, we will conduct a clinical trial and laboratory experiments to determine whether administering BPI will bind endotoxin and shield patients from endotoxin-induced inflammatory responses that trigger transplant toxicity including aGVHD. ? ? ?
| Janec, Kenneth J; Yuan, Huaiping; Norton, James E et al. (2018) rBPI21 (Opebacan) Promotes Rapid Trilineage Hematopoietic Recovery in a Murine Model of High-Dose Total Body Irradiation. Am J Hematol : |
| Guinan, Eva C; Palmer, Christine D; Mancuso, Christy J et al. (2014) Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin. Innate Immun 20:697-711 |
| Guinan, Eva C; Barbon, Christine M; Kalish, Leslie A et al. (2011) Bactericidal/permeability-increasing protein (rBPI21) and fluoroquinolone mitigate radiation-induced bone marrow aplasia and death. Sci Transl Med 3:110ra118 |
| Palmer, Christine D; Guinan, Eva C; Levy, Ofer (2011) Deficient expression of bactericidal/permeability-increasing protein in immunocompromised hosts: translational potential of replacement therapy. Biochem Soc Trans 39:994-9 |
