Specific destruction of hybridoma cells by antigen-toxin conjugates demonstrate an efficient strategy for targeted drug therapy in leukemias of the B cell lineage.
Many types of leukemia including multiple myeloma remain essentially incurable despite recent developments in immuno- and chemotherapy. The effectiveness of these therapies might be greatly enhanced by targeting cell surface proteins unique to the malignant clone, which for leukemias of the B cell lineage means clonotypic surface immunoglobulin (sIg). As this immunoglobulin (Ig) is necessarily epitope specific, we are developing ligand-toxin conjugates (LTCs) as a strategy for delivering toxins and other drugs to clonotypic tumor cells. Here we report in vitro studies that illustrate the effectiveness of this approach. LTC comprising the DNP hapten conjugated to ricin A toxin (DNP-RTA) were shown to specifically and effectively kill anti-DNP secreting murine hybridoma (U7.6) cells but not other hybridoma cells (1B12), a murine erythroleukemia cell line (Friend's Leukemia or) normal mouse spleen cells. In addition to direct toxicity, LTC treatment negatively affected the growth characteristics of the few surviving cells as reflected in decreased growth index and an increase in growth inhibition over 72 h post treatment. Interestingly, U7.6 cells that survived one or two LD90 dose(s) of LTC showed no alteration in their dose response to a subsequent attack of LTC indicating that this treatment strategy may not induce drug resistance. These data suggest that LTC therapy may be a new and effective strategy for specific destruction of tumor cells such as myeloma plasma cells and could be extended to other tumors where clonotypic receptors can be identified.
Firer
Michael A
MA
Immunology Laboratory, Dept. Chemical Engineering and Biotechnology, College Judea and Samaria, P.O. Box 3, Ariel 44837 Israel. firer@research.yosh.ac.il
Laptev
Raisa
R
Kasatkin
Ilena
I
Trombka
David
D
D000818:Animals; D000941:Antigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology*; D002455:Cell Division; D002460:Cell Line; D019070:Cell Lineage; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D000939:Epitopes; D005434:Flow Cytometry; D006801:Humans; D006825:Hybridomas / Q000378:metabolism*; D007136:Immunoglobulins / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008856:Microscopy, Fluorescence; D013045:Species Specificity; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D014118:Toxins, Biological / Q000378:metabolism
D000941:Antigens; D000939:Epitopes; D007136:Immunoglobulins; D008024:Ligands; D014118:Toxins, Biological