Supersaturating infusional humanized anti-CD33 monoclonal antibody HuM195 in myelogenous leukemia.
Humanized anti-CD33 monoclonal antibody HuM195 specifically targets myeloid leukemias in vivo and has been shown to produce molecular remissions in patients with acute promyelocytic leukemia who are in clinical remission. Previous human trials have used low intermittent dosing of HuM195 at 3 mg/m2/day, which is adequate to saturate all available CD33 sites in vivo. In the current trial, we investigated supersaturating doses of HuM195. Ten patients with relapsed or refractory myelogenous leukemia (nine acute myelogenous leukemias and one chronic myelogenous leukemia) were treated on days 1-4 and 15-18 with a 4-h daily infusion of HuM195 at three different dose levels: 12, 24, and 36 mg/m2/day. The total maximum dose of HuM195 was 576 mg. The most common toxicities were grade II fever and rigors, seen more frequently at the highest dose. Interestingly, a transient and reversible drop in hemoglobin of 1-3 g/dl was seen during the infusion in several patients. Flow cytometric analysis showed that antigen sites in the peripheral blood and bone marrow (BM) remained saturated with HuM195 during the entire 4-week trial period. At these high doses, the average plasma half-life of HuM195 was approximately 1 week, compared to 38 h, seen in previous studies. Human anti-HuM195 immune responses were not observed. One patient with acute myelogenous leukemia, whose disease was refractory to two rounds of chemotherapy, with < 10% blasts in his BM, achieved a complete remission, lasting > 32 months, at the first dose level. Another three patients showed a reduction in leukemic BM cells. These studies suggest that high doses of HuM195 achieve a long serum half-life, with tolerable toxicity and without immunogenicity. In addition, antileukemic activity was seen.
Caron
P C
PC
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Dumont
L
L
Scheinberg
D A
DA
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000097:blood / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000097:blood / Q000276:immunology*; D001752:Blast Crisis; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D063268:Sialic Acid Binding Ig-like Lectin 3
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; C101579:monoclonal antibody M195