Manning Michael L, Mason-Osann Emily, Onda Masanori, Pastan Ira
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20894.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20894
J Immunol. 2015 Feb 15;194(4):1695-701. doi: 10.4049/jimmunol.1402324. Epub 2015 Jan 5.
Recombinant immunotoxin (RIT) therapy is limited in patients by neutralizing Ab responses. Ninety percent of patients with normal immune systems make neutralizing Abs after one cycle of RIT, preventing repeated dosing. Furthermore, some patients have pre-existing Abs from environmental exposure to Pseudomonas exotoxin, the component of the RIT that elicits the neutralizing Ab response. Bortezomib is an U.S. Food and Drug Administration-approved proteasome inhibitor that selectively targets and kills plasma cells that are necessary for the neutralizing Ab response. We hypothesized that bortezomib may abrogate neutralizing Ab levels, making dosing of RIT possible in mice already immune to RIT. We immunized BALB/c mice with multiple doses of SS1P, a RIT whose Ab portion targets mesothelin. Mice with elevated Ab levels were separated into groups to receive saline, bortezomib, the pentostatin/cyclophosphamide (PC) regimen, or the bortezomib/PC (BPC) combination regimen. Four weeks after finishing therapy, plasma Ab levels were assayed, and bone marrow was harvested. The bortezomib and PC regimens significantly reduced Ab levels, and we observed fewer plasma cells in the bone marrow of bortezomib-treated mice but not in PC-treated mice. The BPC combination regimen almost completely eliminated Abs and further reduced plasma cells in the bone marrow. This regimen is more effective than individual regimens and may reduce Ab levels in patients with pre-existing neutralizing Abs to Pseudomonas exotoxin, allowing RIT treatment.
重组免疫毒素（RIT）疗法在患者中受到中和抗体反应的限制。90%免疫系统正常的患者在接受一个周期的RIT治疗后会产生中和抗体，从而无法重复给药。此外，一些患者因环境接触绿脓杆菌外毒素而预先存在抗体，绿脓杆菌外毒素是RIT中引发中和抗体反应的成分。硼替佐米是一种经美国食品药品监督管理局批准的蛋白酶体抑制剂，它能选择性地靶向并杀死中和抗体反应所需的浆细胞。我们推测硼替佐米可能会消除中和抗体水平，使已对RIT免疫的小鼠能够接受RIT给药。我们用多剂量的SS1P免疫BALB/c小鼠，SS1P是一种RIT，其抗体部分靶向间皮素。将抗体水平升高的小鼠分成几组，分别接受生理盐水、硼替佐米、喷司他丁/环磷酰胺（PC）方案或硼替佐米/PC（BPC）联合方案治疗。治疗结束四周后，检测血浆抗体水平，并采集骨髓。硼替佐米和PC方案显著降低了抗体水平，我们观察到硼替佐米治疗的小鼠骨髓中的浆细胞较少，但PC治疗的小鼠骨髓中浆细胞数量未减少。BPC联合方案几乎完全消除了抗体，并进一步减少了骨髓中的浆细胞。该方案比单一方案更有效，可能会降低预先存在针对绿脓杆菌外毒素的中和抗体的患者的抗体水平，从而使RIT治疗成为可能。
