Mouse monoclonal antibody M195 (mAb M195), and CDR grafted humanized version (HuG1), anti-CD33, are specifically reactive with myelogenous leukemia cells and myeloid progenitor cells, but not with normal tissues or hematopoietic stem cells. The recombinant HuG1 is similar to the mouse M195, but it has higher affinity and is entirely of human sequences, outside of the antigen binding site. Our pilot trials in humans -have shown that mAb M 195 can rapidly, and efficiently target to leukemia cells in the blood and bone marrow. When 131-I is attached to M195, marked cytoreduction and marrow ablation can be achieved in patients without side effects. Thus, the fundamental goals for the use of mAb for cancer therapy (specificity, potency, nontoxicity), have been reasonably well achieved in this system. The most important next question is Whether this type of therapy can be rationally modeled into a predictive science. If the ablative effects of 131-I-M 195 could be modeled and simulated accurately, this safer form of therapy might ultimately replace total body irradiation (TBI). This therapy differs dramatically from conventional therapies in that much of the injected M195 dose is targeted to the tumor site and therefore dosing must be based on tumor burden as well as on body size. This grant proposes two trials in patients with chronic myelogenous, leukemia (CML) that take advantage of the established specificity and activity of the M195 system to answer this and related questions. There is no curative or even life prolonging therapy for patients with CML, other than for a small fraction of people eligible for allogeneic bone marrow transplantation (BMT). Trial #1 is a phase la/lb trial of 131-I-Ml95 as a marrow ablative preparative regimen before a second BMT in CML. Although patients with blastic CML who have relapsed after BMT generally rapidly die, the first patient treated with this approach in our pilot trial remained in unmaintained remission for 9 months. Trial #2 is a phase Ib dosimetry trial of trace labeled 131-I-HuG1. Three Programs will study: (1) Host immunologic response and tumor response parameters. (2) Pharmacology and dosimetry modeling of 131-I-M195 and 131-HuG1 M195. (3) CML biology and host-donor chimerism during and after this treatment. These trials will involve the interdepartmental efforts of the Clinical Immunology Service, Nuclear Medicine Service, Bone Marrow Transplantation Service, Leukemia Service, and Medical Physics, all at Memorial Sloan-Kettering Cancer Center.
