Antibodies cross-reactive with E- and P-selectin block both E- and P-selectin functions.
E- and P-selectin are inflammation-induced cell adhesion molecules that mediate leukocyte-endothelial cell and leukocyte-platelet interactions. Monoclonal antibodies (MoAbs) specific for either E-selectin or P-selectin are protective in several animal models of inflammatory disease. To generate an MoAb with broader therapeutic potential, MoAbs that bind to both E- and P-selectin were generated by immunization of mice with mouse pre-B cell lines transfected with human E- and P-selectin. Interestingly, although the only selection criterion was the ability to bind both E- and P-selectin, all three antibodies obtained efficiently block both E- and P-selectin-mediated functions. The inhibited functions include neutrophil or HL-60 cell binding to tumor necrosis factor-alpha-activated human umbilical vein endothelial cells, E- or P-selectin transfectant cell lines, and platelet-HL-60 rosetting. These antibodies, EP-5C7, EP-2C9, and EP-1D8, recognize the same or overlapping epitope within the lectin domains of E- and P-selectin. The data suggest that functionally important epitopes of homologous proteins can be targeted by selecting for antibodies with reactivity toward both proteins. Furthermore, a potent blocking antibody specific for both E- and P-selectin may provide a more effective and broadly useful reagent for treating acute and potentially certain chronic inflammatory conditions.
Berg
E L
EL
Protein Design Labs, Inc. Mountain View, CA 94043.
Fromm
C
C
Melrose
J
J
Tsurushita
N
N
D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000494:pharmacology; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000276:immunology; D001667:Binding, Competitive; D001792:Blood Platelets / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D012397:Rosette Formation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000906:Antibodies; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D000939:Epitopes; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha