| Abstract: |
Humanized M195 (HuM195) is a genetically engineered, human IgG1 Version of the parent M195, a mouse immunoglobulin G2a, anti-CD33 monoclonal antibody which reacts with early myeloid progenitor cells and myelogenous leukemia cells. In Phase I studies in patients with relapsed and refractory myelogenous leukemia, HuM195 safely targeted to sites of disease and was nonimmunogenic. HuM195 shows only modest capability of antibody-dependent cellular cytotoxicity (ADCC) against target HL60 cells and minimal cytolytic activity mediated by human complement. Therefore, efforts were made to enhance ADCC using cytokines. Y-Interferon, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor did not promote neutrophil-mediated ADCC with HuM195. However, interleukin-2 (IL-2) showed a range of 2-6-fold increases in ADCC against fresh myelogenous leukemia cells and HL60 cells over that seen with HuM195 or low-dose IL-2 alone. ADCC potency was not improved further by the use of homodimeric HuM195. Flow cytometry and Fc receptor-blocking experiments showed that CD16+ cells were essential for IL-2-enhanced ADCC. As compared to HL60 cells, a multidrug-resistant line of HL60 cells was at least as susceptible to killing by IL-2 or HuM195 or in combination, suggesting that the mechanism of killing may be active against cells surviving and resistant to chemotherapy. Since these in vitro levels of IL-2 and HuM195 can be safely achieved in patients, the enhancement of HuM195 ADCC with low-dose IL-2 is a possible strategy that may be used in vivo to eliminate minimal disease in future trials of patients with myeloid leukemias. © 1995, American Association for Cancer Research. All rights reserved. |
| Keywords: |
controlled study; human cell; antineoplastic agents; animal; mice; cell survival; interleukin 2; cytotoxicity; in vitro study; tumor cells, cultured; mice, inbred balb c; monoclonal antibody; cytokines; antibodies, monoclonal; interferon-gamma, recombinant; leukemia cell; leukemia, myeloid; recombinant proteins; receptors, igg; antigens, cd; granulocyte colony-stimulating factor; interleukin-2; myeloid leukemia; k562 cells; granulocyte-macrophage colony-stimulating factor; monoclonal antibody m 195; receptors, fc; hl-60 cells; cell strain hl 60; antibody-dependent cell cytotoxicity; human; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s.
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