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A Monoclonal Antibody That Induces Neuronal Apoptosis Binds a Metastasis Marker¹

Interdepartmental Program in Neuroscience [L. Z., S. R.], Mental Retardation Research Center [A. L. F.], and Department of Psychiatry and Biobehavioral Sciences and the Neuropsychiatric Institute [K. F. F.], University of California, Los Angeles, California 90024; Program on Aging, The Burnham Institute, La Jolla, California 92037 [L. Z., S. R.]; Glycobiology Program, Cancer Center, University of California, La Jolla, California 92093 [A. M.]; Lawrence Livermore National Laboratory, Livermore, California 94551 [E. S.]; Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305-5125 [L. N.]; Glyko, Inc., Novato, California 94949 [I. M.]; VivoRx, Inc., Santa Monica, California 90404-2429 [M. V-N.]; Biomedical Sciences Graduate Program, University of California, San Francisco, California 94143 [Y. R.]; Department of Psychology, University of California, Los Angeles, California 90095-1563 [J. D. O., L. L. B.]; and Buck Institute for Age Research, Novato, California 94945 [D. E. B.]

The cell surface molecules controlling apoptosis in cortical neurons are largely unknown. A monoclonal antibody was derived that induces cultured neocortical neurons to undergo apoptosis. A Fab fragment of the antibody, however, lacked the ability to induce cell death. The antigen was purified, and characterized by compositional analysis, fast atom bombardment (FAB) mass spectrometry, sequential exoglycosidase treatments, methylation analysis, and ¹H-nuclear magnetic resonance spectroscopy, proving to be isoglobotetraosylceramide (IsoGb4). IsoGb4 has been shown previously to be a metastasis marker, antibodies against which block metastases in a mammary adenocarcinoma model (S. A. Carlsen et al., Cancer Res., 53: 2906–2911, 1993). Addition of the purified antigen to cells lacking this glycolipid demonstrated that it is capable of functioning as a portable apoptosis-transducing molecule. Intracellular ceramide levels were increased after the treatment with the apoptosis-inducing antibody, but the membrane sphingomyelin level remained unchanged. Fumonisin B1 inhibited both the ceramide increase and the apoptosis induced via IsoGb4, which indicated that the ceramide synthase pathway is likely to be involved in apoptosis induction by IsoGb4.