RADIOLABELED ANTI-CD33 MONOCLONAL-ANTIBODY M195 FOR MYELOID LEUKEMIAS

M195, a mouse monoclonal antibody reactive with the early myeloid anti gen CD33, has been shown to target leukemia cells in patients and to r educe large leukemic burdens when labeled with I-131, A complementarit y-determining region-grafted, humanized version (HuM195) has demonstra ted similar targeting of leukemia cells without immunogenicity, We hav e studied two applications of therapy with I-131-M195. First, to inten sify therapy prior to bone marrow transplantation (BMT), we combined I -131-M195 with busulfan and cyclophosphamide, Fifteen patients receive d first BMT for relapsed or refractory acute myelogenous leukemia or a ccelerated or blastic chronic myelogenous leukemia; four received seco nd BMT for relapsed chronic or accelerated chronic myelogenous leukemi a. Doses of I-131-M195 ranged from 120 to 230 mCi/m(2). Few toxicities could be attributed to I-131-M195 therapy, and all patients engrafted , Eighteen patients achieved complete remission, Among those patients receiving first BMT, three have remained in unmaintained remission for 18+ to 29+ months, Six patients relapsed, including one with isolated central nervous system disease 32 months after BMT, Ten patients died in complete remission of transplant-related complications, Second, we studied whether I-131-M195 could reduce minimal residual disease and prolong remission and survival durations safely in patients with relap sed acute promyelocytic leukemia after they attained remission with al l-trans-retinoic acid. Seven patients were treated with either 50 or 7 0 mCi/m(2) I-131-M195, Toxicity was limited to myelosuppression, As a measure of minimal residual disease, we monitored PML/RAR-alpha mRNA b y reverse transcription PCR, Six patients had positive reverse transcr iption PCR assays prior to receiving I-131-M195; two converted transie ntly to negative, Median disease-free survival and overall survival of the seven patients were 8 (range, 3-14.5) months and 28 (range, 5.5-4 3+) months, respectively. This regimen compares favorably with others for relapsed acute promyelocytic leukemia, In an effort to avoid nonsp ecific cytotoxicity associated with I-131 in future trials for minimal residual disease, we have conjugated short-range, alpha particle-emit ting radioisotopes to HuM195 using a bifunctional chelate, 2-(p-isothi ocyanatobenzyl)-cyclohexyldiethyl- enetriaminepentaacetic acid, with h igh efficiency and specific activities, Bi-212-HuM195 has demonstrated dose- and specific activity-dependent killing of HL60 cells in vitro, Injection of Bi-213-HuM195 into healthy BALB/c mice produced no effec ts on weight or viability.