IFN-gamma enhances the antimyeloma activity of the fully human anti-human leukocyte antigen-DR monoclonal antibody 1D09C3.
To investigate the therapeutic activity of the fully human anti-HLA-DR antibody 1D09C3 in multiple myeloma (MM), we reevaluated HLA-DR expression on CD138(+) cells, analyzed the capacity of IFN-gamma to up-regulate HLA-DR expression on MM cell lines, and tested the in vitro and in vivo activity of 1D09C3 alone or in combination with IFN-gamma. CD138(+)HLA-DR(+) cells were detected in 31 of 60 patients, with 15 of 60 patients having >/=20% CD138(+)HLA-DR(+) cells (median, 50%; range, 23-100). Because primary plasma cells cannot be efficiently cultured in vitro, we used a panel of MM cell lines with a dim/negative to bright HLA-DR expression to evaluate 1D09C3-induced cell death. Annexin V/propidium iodide (PI) staining showed that 1D09C3-induced cell death correlated with constitutive HLA-DR expression. Induction of HLA-DR by IFN-gamma restored the sensitivity of HLA-DR dim cell lines to 1D09C3. In vivo, the combined IFN-gamma/1D09C3 treatment significantly increased the median survival of nonobese diabetic/severe combined immunodeficient mice xenografted with KMS-11 cell line, compared with controls (147 versus 48 days, P </= 0.0001) or mice receiving 1D09C3 alone (147 versus 92 days, P </= 0.03). The better therapeutic activity of IFN-gamma/1D09C3 treatment over 1D09C3 alone was further shown by a 2-fold increase of mice being disease-free at 150 days after xenograft (47% versus 25%). No mice experienced any apparent treatment-related toxicity. Our data show that (a) one fourth of MM patients express HLA-DR on CD138(+) cells and (b) IFN-gamma-induced up-regulation of HLA-DR results in a potent enhancement of the in vivo antimyeloma activity of 1D09C3.
Carlo-Stella
Carmelo
C
"Cristina Gandini" Medical Oncology Unit, Medical Oncology, University of Milano, Milan, Italy.
Guidetti
Anna
A
Di Nicola
Massimo
M
Lavazza
Cristiana
C
Cleris
Loredana
L
Sia
Daniela
D
Longoni
Paolo
P
Milanesi
Marco
M
Magni
Michele
M
Nagy
Zoltan
Z
Corradini
Paolo
P
Carbone
Antonino
A
Formelli
Franca
F
Gianni
Alessandro M
AM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D011994:Recombinant Proteins; D053668:Syndecan-1 / Q000276:immunology; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D006684:HLA-DR Antigens; D011994:Recombinant Proteins; C508241:SDC1 protein, human; D053668:Syndecan-1; D007371:Interferon-gamma