Interleukin-2 enhancement of cytotoxicity by humanized monoclonal antibody M195 (anti-CD33) in myelogenous leukemia.

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. gamma-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.

• Authors: P C Caron, L T Lai, D A Scheinberg
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 1 Issue 1 Pg. 63-70 (Jan 1995) ISSN: 1078-0432 [Print] United States
• PMID: 9815888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• Antineoplastic Agents
• Cytokines
• Interleukin-2
• Receptors, Fc
• Receptors, IgG
• Recombinant Proteins
• monoclonal antibody M195
• Granulocyte Colony-Stimulating Factor
• Interferon-gamma
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Animals
• Antibodies, Monoclonal (toxicity)
• Antibody-Dependent Cell Cytotoxicity (drug effects, physiology)
• Antigens, CD (physiology)
• Antineoplastic Agents (toxicity)
• Cell Survival (drug effects)
• Cytokines (pharmacology)
• Granulocyte Colony-Stimulating Factor (pharmacology)
• Granulocyte-Macrophage Colony-Stimulating Factor (pharmacology)
• HL-60 Cells
• Humans
• Interferon-gamma (pharmacology)
• Interleukin-2 (pharmacology)
• K562 Cells
• Leukemia, Myeloid (drug therapy, immunology, pathology)
• Mice
• Mice, Inbred BALB C
• Receptors, Fc (physiology)
• Receptors, IgG (physiology)
• Recombinant Proteins (pharmacology)
• Tumor Cells, Cultured