Bispecific antibodies reactive with the multidrug-resistance-related glycoprotein and CD3 induce lysis of multidrug-resistant tumor cells.
We describe the lysis of multidrug-resistant (MDR) tumor cells by various lymphocytic effector cells, retargeted with bispecific antibodies (heteroconjugates). The Ab-heteroconjugate used was prepared by chemically cross-linking the OKT3 monoclonal antibody (MAb) reactive with CD3 antigen on T lymphocytes, with the MRK16 MAb, which recognizes the MDR-associated P-glycoprotein. Cloned TCR alpha beta/CD3+ T lymphocytes, OKT3-activated peripheral-blood mononuclear cells and peripheral-blood mononuclear blood lymphocytes, stimulated with allogeneic irradiated cells in a mixed lymphocyte culture, could be induced to lyse MDR ovarian tumor cells in the presence of Ab-heteroconjugate CD3/MRK16, whereas the drug-sensitive parental tumor cells lacking the P-glycoprotein were not lysed by these retargeted effector cells. Cloned TCR gamma delta/CD3+ T lymphocytes showed a high MHC-unrestricted lysis of MDR tumor cells. Addition of Ab-heteroconjugate CD3/MRK16 could therefore not enhance target-cell lysis. Melanoma tumor cells transfected with the mdr-I gene which codes for the P-glycoprotein were also efficiently lysed by Ab-heteroconjugate retargeted cloned TCR alpha beta/CD3+ T cells. Tumor cell lines derived from organs known to express the P-glycoprotein also were lysable by the retargeted effector cells.
Van Dijk
J
J
Department of Pathology, State University Leiden, The Netherlands.
Tsuruo
T
T
Segal
D M
DM
Bolhuis
R L
RL
Colognola
R
R
van de Griend
R J
RJ
Fleuren
G J
GJ
Warnaar
S O
SO
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology*; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D004351:Drug Resistance / Q000276:immunology; D005434:Flow Cytometry; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D009369:Neoplasms / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D006023:Glycoproteins