Bethge Wolfgang A, Wilbur D Scott, Storb Rainer, Hamlin Donald K, Santos Erlinda B, Brechbiel Martin W, Sandmaier Brenda M
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Transplantation. 2004 Aug 15;78(3):352-9. doi: 10.1097/01.tp.0000128853.62545.b2.
Using a canine model of nonmyeloablative hematopoietic cell transplantation (HCT), the authors demonstrated that pretransplant radioimmunotherapy with the alpha-emitter bismuth-213 (Bi) coupled to anti-CD45 or anti-T-cell receptor alphabeta (TCRalphabeta) monoclonal antibodies (mAb), together with postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine A (CsA), achieved stable engraftment of dog leukocyte antigen (DLA)-identical marrow. Engraftment was achieved with doses of 3.6 to 8.8 mCi/kg Bi, but signs of liver toxicity were noted in all dogs. To find a safe and effective dose for further trials, the authors performed a dose deescalation study in 15 dogs with 2.7 to 0.8 mCi/kg Bi.
Bi was linked to the mAb using the metal-binding chelate CHX-A"-DTPA. All dogs received three to six injections of Bi linked to anti-CD45 or anti-TCRalphabeta mAb followed by marrow grafts from DLA-identical littermates and postgrafting MMF and CsA.
During follow-up of greater than 30 weeks, engraftment remained stable in all evaluable dogs conditioned with 1.4 to 2.1 mCi/kg Bi-anti-CD45 or 2.0 to 2.7 mCi/kg Bi-anti-TCRalphabeta. Only one dog conditioned with 1.5 mCi/kg Bi-anti-TCRalphabeta had stable engraftment, whereas two rejected their grafts. In both groups, all dogs conditioned with less than 1.3 mCi/kg Bi rejected their grafts. No signs of graft-versus-host disease or other toxicities were noted. Only mild and transient elevation of liver function tests occurred in 4 of 15 dogs.
This study demonstrates that dose deescalation of radioimmunotherapy with Bi labeled to anti-CD45 or anti-TCRalphabeta as conditioning for nonmyeloablative HCT minimizes toxicity without compromising engraftment. With a dose of 2 mCi/kg Bi, further trials using radioimmunotherapy with Bi for nonmyeloablative HCT seem feasible.
作者利用犬类非清髓性造血细胞移植（HCT）模型证明，移植前使用与抗CD45或抗T细胞受体αβ（TCRαβ）单克隆抗体（mAb）偶联的α发射体铋-213（Bi）进行放射免疫治疗，联合移植后使用霉酚酸酯（MMF）和环孢素A（CsA）进行免疫抑制，可实现犬白细胞抗原（DLA）匹配的骨髓稳定植入。使用3.6至8.8 mCi/kg的Bi剂量可实现植入，但所有犬均出现肝毒性迹象。为了找到进一步试验的安全有效剂量，作者对15只犬进行了剂量递减研究，Bi剂量为2.7至0.8 mCi/kg。
使用金属螯合剂CHX-A”-DTPA将Bi与mAb连接。所有犬接受三至六次与抗CD45或抗TCRαβ mAb偶联的Bi注射，随后接受来自DLA匹配的同窝仔犬的骨髓移植以及移植后MMF和CsA治疗。
在超过30周的随访期间，所有接受1.4至2.1 mCi/kg Bi-抗CD45或2.0至2.7 mCi/kg Bi-抗TCRαβ预处理的可评估犬的植入情况保持稳定。仅一只接受1.5 mCi/kg Bi-抗TCRαβ预处理的犬植入稳定，而两只犬排斥了移植。在两组中，所有接受低于1.3 mCi/kg Bi预处理的犬均排斥了移植。未观察到移植物抗宿主病或其他毒性迹象。15只犬中有4只仅出现肝功能检查轻度和短暂升高。
本研究表明，以与抗CD45或抗TCRαβ偶联的Bi进行放射免疫治疗作为非清髓性HCT的预处理进行剂量递减，可在不影响植入的情况下将毒性降至最低。使用2 mCi/kg Bi的剂量，进一步开展使用Bi进行非清髓性HCT放射免疫治疗的试验似乎是可行的。
