Interferon-alpha enhances CD317 expression and the antitumor activity of anti-CD317 monoclonal antibody in renal cell carcinoma xenograft models.
A murine (mAHM) and a humanized (AHM) monoclonal antibody against CD317 (also called tetherin, BST2, or HM1.24 antigen), expressed preferentially in neoplastic B cells such as multiple myeloma, exhibited antitumor effects as a result of antibody-dependent cellular cytotoxicity (ADCC). The putative interferon (IFN) response elements IRF-1/2 and ISGF3 are present in the promoter of the CD317 gene, and IFN has been used for the treatment of not only myeloproliferative diseases but also solid tumors such as renal cell carcinoma (RCC) and melanoma. Therefore, we examined the effects of IFN on the expression of CD317 and on the antitumor activity of AHM and mAHM in RCC and melanoma. Flow cytometry and in vitro ADCC assays with human or mouse effector cells demonstrated that IFN-alpha markedly increased the amount of cell surface CD317 and augmented the ADCC activity of mAHM and AHM in RCC cells and to a lesser extent in melanoma cells. Administration of IFN-alpha to mice bearing RCC xenografts also increased the expression of CD317 in tumor cells. When coadministered with IFN-alpha, mAHM exhibited more profound antitumor activity in both IFN-alpha-sensitive and -insensitive RCC xenograft models. Thus, AHM in combination with IFN-alpha may be an effective therapy for the treatment of RCC.
Kawai
Shigeto
S
Pharmaceutical Research Department, Chugai Pharmaceutical, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Azuma
Yumiko
Y
Fujii
Etsuko
E
Furugaki
Kou
K
Ozaki
Shuji
S
Matsumoto
Toshio
T
Kosaka
Masaaki
M
Yamada-Okabe
Hisafumi
H
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D058851:GPI-Linked Proteins; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D000074010:Bone Marrow Stromal Antigen 2
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D058851:GPI-Linked Proteins; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2