Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD2 monoclonal antibody, MEDI-507.

Abstract

Adult T-cell leukemia (ATL) develops in a small proportion of individuals infected with the retrovirus human T-cell leukemia virus (HTLV-1). We evaluated the efficacy of MEDI-507 (a humanized monoclonal antibody directed against CD2) alone and in combination with humanized anti-Tac (HAT) directed toward CD25, the interleukin-2 receptor alpha (IL-2Ralpha) using a human adult T-cell leukemia xenograft model. Weekly treatments (4) with HAT significantly prolonged the survival of the ATL-bearing mice when compared with phosphate-buffered saline (PBS)-treated controls (P <.0001). Mice treated with MEDI-507 (100 microg/wk for 4 weeks) survived longer than those treated with HAT (P <.0025). Furthermore, prolonged treatment (6 months) of ATL with MEDI-507 significantly improved the outcome when compared with a short course (4 weeks) of therapy (P <.0036). Such treatment with weekly MEDI-507 for 6 months led to a prolonged survival of the ATL-bearing mice that was comparable with the survival observed in the control group of mice that did not receive a tumor or therapeutic agent. We also found that the expression of Fcgamma receptors (FcRgamma) on polymorphonuclear leukocytes and monocytes was required for MEDI-507-mediated tumor killing in vivo. Thus, the tumor-killing mechanism with MEDI-507 in vivo required the expression of the receptor FcRgammaIII on polymorphonuclear leukocytes and monocytes, suggesting that it is mediated by a form of antibody-dependent cellular cytotoxicity. These results demonstrate that MEDI-507 has therapeutic efficacy on ATL in vivo and provides support for a clinical trial involving this monoclonal antibody in the treatment of patients with CD2-expressing leukemias and lymphomas.

• Authors: Zhuo Zhang, Meili Zhang, Jeffrey V Ravetch, Carolyn Goldman, Thomas A Waldmann
• Journal: Blood (Blood) Vol. 102 Issue 1 Pg. 284-8 (Jul 01 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12649132 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• CD2 Antigens
• IL2RA protein, human
• Il2ra protein, mouse
• Interleukin-2 Receptor alpha Subunit
• Receptors, IgG
• Receptors, Interleukin
• Receptors, Interleukin-2
• siplizumab

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• CD2 Antigens (immunology)
• Disease Models, Animal
• Humans
• Interleukin-2 Receptor alpha Subunit
• Leukemia-Lymphoma, Adult T-Cell (drug therapy)
• Mice
• Mice, Knockout
• Receptors, IgG (genetics, physiology)
• Receptors, Interleukin (immunology)
• Receptors, Interleukin-2 (immunology)
• Survival Analysis
• Transplantation, Heterologous
• Treatment Outcome