TY - JOUR
T1 - IgM monoclonal antibody JD118 recognizes an inducible antigen target for human-complement-mediated cytotoxicity against neoplastic B cells
AU - Czuczman, Myron S.
AU - Garin-Chesa, Pilar
AU - Lemoli, Roberto M.
AU - Scheinberg, David A.
PY - 1993/11
Y1 - 1993/11
N2 - 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 105 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.
AB - 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 105 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.
KW - Antigen upregulation
KW - B cell neoplasms
KW - Complement-dependent cytotoxicity
KW - IgM
KW - Monoclonal antibodies
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U2 - 10.1007/BF01742255
DO - 10.1007/BF01742255
M3 - Article
C2 - 8500111
AN - SCOPUS:0027255922
VL - 36
SP - 387
EP - 396
JO - Cancer Immunology and Immunotherapy
JF - Cancer Immunology and Immunotherapy
SN - 0340-7004
IS - 6
ER -