Cocktails of ricin A-chain immunotoxins against different antigens on Hodgkin and Sternberg-Reed cells have superior anti-tumor effects against H-RS cells in vitro and solid Hodgkin tumors in mice.
Three ricin A-chain immunotoxins (ITs) recognizing different antigens on Hodgkin-Reed/Sternberg (H-RS) cells were evaluated for their anti-tumor effects when used in combination as "cocktails". These ITs, BB10.dgA (CD25), HRS3.dgA (CD30), and IRac.dgA (70 kDa), strongly inhibited the growth of L540Cy H-RS cells in vitro. The protein synthesis of this cell line was reduced more efficiently by the combination of 2 of these ITs than by BB10.dgA, HRS3.dgA or IRac.dgA alone. A cocktail of all 3 ITs was most effective in vitro. This was at least in part due to the non-homogeneous distribution of CD25, CD30 or IRac on the L540Cy H-RS target cells and to the fact that subpopulations deficient in one antigen nevertheless expressed appreciable levels of the other target antigens. IT cocktails were also superior as anti-tumor agents in nude mice with solid L540Cy tumors. Ninety percent of mice treated with cocktails containing 2 or 3 ITs had continuous complete remissions (CCR), as compared with only 40% of mice treated with the same dose of a single IT. Analysis of 7 L540Cy sub-lines re-established ex vivo from mice that relapsed after having achieved complete remission (CR) after therapy with a single IT showed that the surviving tumor cells were antigen-deficient variants which were resistant to the original IT, but which could be killed by ITs directed against other target antigens. Thus, IT cocktails give superior results against human H-RS cells, both in vitro and in vivo.
Engert
A
A
Klinik I für Innere Medizin, University of Cologne, Germany.
Gottstein
C
C
Bohlen
H
H
Winkler
U
U
Schön
G
G
Manske
O
O
Schnell
R
R
Diehl
V
V
Thorpe
P
P
D000818:Animals; D006689:Hodgkin Disease / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D000922:Immunotoxins / Q000627:therapeutic use*; D017730:Ki-1 Antigen / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage; D015375:Receptors, Interleukin-2 / Q000276:immunology; D016539:Reed-Sternberg Cells / Q000276:immunology*; D012276:Ricin / Q000008:administration & dosage*
D000922:Immunotoxins; D017730:Ki-1 Antigen; D011500:Protein Synthesis Inhibitors; D015375:Receptors, Interleukin-2; D012276:Ricin