MURINE AND HUMANIZED CONSTRUCTS OF MONOCLONAL-ANTIBODY M195 (ANTI-CD33) FOR THE THERAPY OF ACUTE MYELOGENOUS LEUKEMIA

Long-term survival rates of patients with acute myelogenous leukemia t reated with intensive chemotherapy are 15-20%, despite efforts to deve lop new treatment strategies. Murine M195 (I-131-M195), an anti-CD33, immunoglobulin (Ig) G2a monoclonal antibody has reactivity restricted to early myeloid cells and myeloid leukemic blasts but not hematopoiet ic progenitors. Previous trials in patients with relapsed or refractor y myeloid leukemia showed that I-131-M195 rapidly targeted to the bone marrow and internalized into target cells. This article describes a t herapeutic dose escalation study in which 24 patients received from 50 mCi/m(2) to 210 mCi/m(2) of I-131-M195 in divided doses. Cytoreductio n of peripheral cell counts and bone marrow blasts occurred without no nhematopoietic toxicity. Doses of I-131-M195 greater than 135 mCi/m(2) were associated with marrow cytoreduction sufficient to necessitate b one marrow transplant. However, 37% of the patients developed human an ti-mouse antibody, preventing retreatment. To decrease immunogenicity and improve effector function, chimeric IgG1 and IgG3, and complementa rity-determining region-grafted, humanized IgG1 and IgG3 versions of m ouse M195 were developed by genetic engineering techniques. The new ve rsions maintained specificity and biologic function, and they were sup erior to the mouse M195 in their ability to perform antibody-dependent cellular cytotoxicity against leukemia cells. Humanized M195, but not chimeric M195, showed a 4-8.6 times higher avidity than its mouse cou nterpart. Because effector function of IgG depends to a large extent o n Fc clustering, a homodimeric HuG1 also was developed. Homodimeric Hu G1 showed an ability to cause additional dramatic improvements in effe ctor functions, as well as an ability to internalize and retain radioi sotope in target leukemia cells. Monomeric and dimeric forms of humani zed M195 may be advantageous in the therapy of acute myelogenous leuke mia. Cancer 1994; 73:1049-56.