IgM monoclonal antibody JD118 recognizes an inducible antigen target for human-complement-mediated cytotoxicity against neoplastic B cells.
Cancer therapy using unconjugated monoclonal antibodies (mAb) has been limited by the lack of immune effector function of the mAb and antigenic modulation. JD118 is a cytotoxic murine IgM mAb with reactivity restricted to a subset of normal B cells, some monocytic series cells, and a large percentage of B cell hematopoietic neoplasms including acute and chronic leukemias and lymphomas. Specificity was determined on several hundred normal and neoplastic, hematopoietic and non-hematopoietic cells and tissues, as well as progenitor cells. JD118 was able to kill fresh human leukemias and lymphomas in the presence of human serum as a complement source with an LD50 of 100 ng/ml. At this mAb concentration, fewer than 4% of more than 10(5) available target sites were bound. Killing was not affected by changes in antigen expression observed during the cell cycle nor by loss of cell-surface targets via antigenic modulation. Cytotoxicity could be achieved with human serum diluted as low as 5%, suggesting that complement depletion in vivo should not limit activity. Autologous human serum could be used effectively as a complement source. The JD118 antigen target has not been identified, but it appears to be a glycoprotein. Up-regulation of antigen expression on normal B cells and chronic lymphocytic leukemia cells in vitro resulted in antigen-negative neoplasms becoming positive and thus targets for JD118 killing. The restricted expression, potent cytotoxic characteristics, and potential for up-regulation of its antigen make JD118 a possible candidate for ex vivo autologous bone marrow purging and in vivo therapeutic trials in patients with B cell neoplasms.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York 10021.
M S
MS
Czuczman
P
P
Garin-Chesa
R M
RM
Lemoli
D A
DA
Scheinberg
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use; D000937:Antigen-Antibody Reactions; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002051:Burkitt Lymphoma / Q000276:immunology* / Q000628:therapy; D002453:Cell Cycle / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000737:chemistry*; D007150:Immunohistochemistry; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007075:Immunoglobulin M; D003165:Complement System Proteins