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Interferon gamma augments Lym-1-dependent, granulocyte-mediated tumor cell
lysis
L Vaickus, W Biddle, D Cemerlic and KA Foon
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263.
Lym-1 is a therapeutically promising IgG2a monoclonal antibody (MoAb) that
reacts with variant class II molecules expressed on B-lineage malignancies.
To optimize antitumor immunotherapy with Lym-1, we determined whether
granulocytes could participate in tumor lysis mediated by Lym-1 and whether
recombinant interferon gamma (IFN-gamma) could influence this reaction.
Granulocytes had minimal activity in mediating Lym-1 antibody-dependent
cellular cytotoxicity (ADCC) compared with peripheral blood mononuclear
cells (PBMC). However, IFN- gamma markedly augmented and occasionally
induced granulocyte Lym-1 ADCC in a dose-dependent fashion (optimal 100
U/mL). Granulocytes primed with IFN-gamma for 24 hours displayed greatly
increased ADCC in the absence of further IFN-gamma exposure. In most
individuals, IFN- gamma also enhanced PBMC Lym-1 ADCC. Interferon alfa
(IFN-alpha), although able to enhance PBMC-mediated Lym-1 ADCC and non-ADCC
lysis, had no effect on granulocyte activity. Lym-1 ADCC involved an
interaction between Fc receptor-bearing granulocytes and Lym-1 antigen
positive targets based on the following: (1) The reaction was Lym-1
dose-dependent with cytotoxicity detectable at concentrations as low as 0.5
microgram/mL. (2) An irrelevant, isotype-matched MoAb (UPC-10) was unable
to mediate ADCC. (3) In the absence of Lym-1, granulocytes--with or without
IFN-gamma--displayed no intrinsic tumor lytic ability. Conversely, without
granulocytes, Lym-1 or Lym-1 plus IFN-gamma had no effect. (4) Protein A,
which binds avidly to Lym-1, inhibited the reaction 95%. (5) IFN-gamma
induced granulocyte expression of CD64, the IgG Fc receptor that binds
murine IgG2a MoAbs. (6) Of nine malignant human cell lines, only the three
that moderately or strongly expressed the Lym-1 antigen were consistently
lysed. Preclinical studies such as these may provide a rational basis for
designing clinical trials with Lym-1 in combination with IFN-gamma.
Volume 75,
Issue 12,
pp. 2408-2416,
06/15/1990
Copyright © 1990 by The American Society of Hematology
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