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

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Caron PC, Lai LT, Scheinberg DA

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

Clin Cancer Res. 1995 Jan;1(1):63-70.

PubMed ID

9815888 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Gemtuzumab ozogamicin	Low affinity immunoglobulin gamma Fc region receptor III-B	Protein	Humans	Unknown	Not Available	Details