Myeloid leukemias of adults remain largely incurable. The long term goals of this program are to develop monoclonal antibody (mAb)-based therapeutic agents for myeloid leukemia. Over the last 2 1/2 years on this RO1, we have constructed new recombinant CDR grafted humanized antiCD33 mAb (HuMl95) and characterized their biology and biochemistry. This renewal grant builds on the prior work and proposes development of a novel alpha emitting HuMl95, study of the native immune function of the mAb in conjunction with cytokines, as well as an exploration of newly observed immunological resistance to HuM195 constructs. Clinical trials with murine M195 have now shown that M195 rapidly targets, saturates and internalizes into myelogenous leukemia cells in different compartments of the body at low doses and, when radiolabeled, can kill more than 99% of leukemia cells even in refractory patients with high leukemia burden (> 1 kg). Murine 131I-M195 is limited by lack of intrinsic effector activity,, bystander cell kin due to the long range beta of iodine-131, and also neutralization by human anti-mouse antibody (HAMA). HuMl95 has recently entered clinical study with similar pharmacology but without immunogenicity. This antigen- antibody-disease system allows tests of applications of potent radiolabeled mAb constructs and native mAb to eliminate minimal residual disease: 1. We will approach the radio-ablative strategy by developing a more feasible alpha-particle emitting HuM 195.
This first aim i s based on newly formulated Bismuth-213 radiochemistry that allows us to purify a chelatable radiometal that does not have dangerous gamma emissions. 2. In vitro, HuMl95 is capable of mediating specific potent antibody-dependent cellular cytotoxicity (ADCC) against myelogenous leukemia cells, particularly in the presence of low doses of IL-2.
A second aim of this study is to explore the interaction of HuM 195 and cytokines in ADCC. 3. We recently observed that MDR HL60 cells were also cross- resistant to HuM 195-based immunotoxins, radioconjugates, and complement-mediated killing.
A third aim proposes to study and explain this new immunological resistance; electrophysical studies will be done on individual cells and on populations. This may have wide implications for immunotherapy. 4. Finally, in order to more quickly study the novel alpha particle emitting constructs we propose to develop a CD33 positive, reproducible leukemia model in mice.
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