Action of a CD24-specific deglycosylated ricin-A-chain immunotoxin in conventional and novel models of small-cell-lung-cancer xenograft.
The therapeutic efficacy of an immunotoxin, SWAII-SPDB-dg.ricin A chain, recognizing the leukocyte-differentiation antigen CD24, was evaluated against SCLC cell lines in tissue culture and in 2 nude-mouse models. The first model used conventional s.c. solid-tumor xenografts. The second used small tumor-cell deposits established in s.c. implanted sponge matrices and allowed us to directly estimate the killing efficiency of the immunotoxin under experimentally defined conditions in vivo. It also mimics the clinical setting of disseminated tumor cells which form the basis of residual disease in SCLC. The cytotoxic potency of SWAII-SPDB-dg.ricin A chain was demonstrated in tissue culture by the inhibition of 3H-leucine incorporation and by the selective elimination of CD24-positive tumor cells in clonogenic assays. In nude mice, SWAII-SPDB-dg.ricin A chain was cleared from the blood circulation with biphasic kinetics: an initial alpha phase of 1 hr and a second beta phase of 20.5 hr. Following i.v. injection of a dose equivalent to 30% of the LD50, the immunotoxin delayed the growth of SW2 solid-tumor xenografts by 16 days. The therapeutic efficacy of SWAII-SPDB-dg.ricin A chain was further demonstrated by the selective elimination of clonogenic SW2 cells from small tumor-cell deposits established in sponge matrices. Regrowth of the solid tumors after the initial response and the clonogenic activity in the sponge-derived cell population were mediated by CD24-positive cells, excluding the selection of CD24-negative mutants during immunotoxin therapy.
Division of Oncology, University Hospital, Zurich, Switzerland.
U
U
Zangemeister-Wittke
H P
HP
Lehmann
R
R
Waibel
E J
EJ
Wawrzynczak
R A
RA
Stahel
D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D051927:CD24 Antigen; D018288:Carcinoma, Small Cell / Q000628:therapy*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006031:Glycosylation; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000628:therapy*; D008562:Membrane Glycoproteins; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012276:Ricin / Q000008:administration & dosage / Q000737:chemistry; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D051927:CD24 Antigen; C497889:CD24 protein, human; C497890:Cd24a protein, mouse; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D012276:Ricin