Evaluation of drug-antibody conjugates in the treatment of human myelosarcomas transplanted in nude mice

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Abstract
Methotrexate, daunomycin, and chlorambucil were independently conjugated to immune goat γ-globulins specifically raised to the Ph1 + chronic myelogenous leukemia cell line K-562. The drug-antibody conjugates were then tested against myelosarcomas made up of K-562 cells growing in nude mice and their efficacy was compared with that of the drug alone, γ-globulins, a mixture of the two, or conjugates of drugs with normal goat γ-globulin. Conjugation methods for methotrexate and daunomycin abrogate the antibody activity as indicated by the absence of complement-mediated cytotoxicity of the conjugates in vitro and the lack of effect on myelosarcomas in vivo. Simultaneous administration of either of these drugs and antibody partially abrogated the development of myelosarcomas. Chlorambucil-antibody conjugates, however, retained their cytotoxicity in vitro and were found effective in vivo. It is the first successful attempt to covalently bind chlorambucil to γ-globulins without the loss of drug or antibody biological activity. Although the simultaneous administration of chlorambucil and γ-globulins and conjugated drug γ-globulins reduced the growth of myelosarcomas considerably, the immune γ-globulins alone either reduced their weight to a larger degree or eliminated their growth completely. Results of this study indicate that myelosarcomas made up of K-562 cells grown in nude mice are good and reproducible models for testing various therapeutic agents. The advantage of using human cells proliferating in an in vivo environment brings experimental therapy one step closer to clinical trials.