The ability to target radiation to hematopoietic tissues may improve the outcome of bone marrow transplantation for acute leukemia and for genetic disorders such as thalassemia and sickle cell anemia by decreasing the relapse rates after transplant, the toxicity of the preparative regimens, and the risk of rejection of T cell depleted HLA-mismatched or unrelated marrow. 131I-anti-CD45 antibody has been demonstrated to deliver greater radiation doses to the marrow, spleen and lymph nodes than to non-target organs in preclinical studies in mice and macaques. Preliminary clinical studies in patients with advanced AML, ALL, or MDS undergoing marrow transplantation have demonstrated the feasibility and tolerability of using 131I-anti-CD45 antibody to deliver supplemental radiation to hematopoietic tissues when combined with cyclophosphamide and total body irradiation (TBI). However, the efficacy of this therapy should improve and toxicity should decrease if the proportion of radiation delivered via antibody could be increased, while decreasing or eliminating the radiation delivered as TBI. The proposed preclinical studies will determine the marrow ablative and immunosuppressive effects of 131I-anti-CD45 antibody by using it, alone or with low dose TBI, as a preparative regimen for mice receiving T-depleted marrow transplants from congenic donors or donors mismatched at minor or major histocompatibility loci. These studies will include the assessment of both early and late toxicities associated with this low-dose-rate radiation delivered by radioimmunoconjugates. Further studies will examine strategies to improve the ratio of radiation delivered to target as compared to normal organs. These will include the effect of a pretargeting method using an antibody-streptavidin conjugate followed at a later time point by an isotope-biotin moiety. The effect of the use of alternative isotopes with a shorter half-life (such as 90Y, 64 hours and 186Re, 90 hours) than 131I (8 days) will be tested, as the highest levels in target tissues occur within the first 48 to 72 hours after antibody administration. The definition of the immunosuppressive and marrow ablative capacity of radiolabeled anti-CD45 antibody, and the optimization of the hematopoietic specificity of such radiation in the proposed preclinical studies, should ultimately allow improved efficacy and decreased toxicity of preparative regimens used in marrow transplantation for leukemia and genetic disorders. It may also support the use of radiolabeled anti-CD45 antibody to decrease both the rejection and relapse rates after T-depleted HLA-mismatched or unrelated donor marrow transplants.
| Nemecek, Eneida R; Hamlin, Donald K; Fisher, Darrell R et al. (2005) Biodistribution of yttrium-90-labeled anti-CD45 antibody in a nonhuman primate model. Clin Cancer Res 11:787-94 |
| Ruffner, K L; Martin, P J; Hussell, S et al. (2001) Immunosuppressive effects of (131)I-anti-CD45 antibody in unsensitized and donor antigen-presensitized H2-matched, minor antigen-mismatched murine transplant models. Cancer Res 61:5126-31 |
