Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma.
MAbs
; 7(2): 311-21, 2015.
Article
em En
| MEDLINE
| ID: mdl-25760767
ABSTRACT
Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA's mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt's lymphoma cell lines. Phagocytosis contributed to DARA's anti-tumor activity in vivo, in both a subcutaneous and an intravenous leukemic xenograft mouse model. Finally, DARA was shown to induce macrophage-mediated phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable levels of CD38 expression. In summary, we demonstrate that phagocytosis is a fast, potent and clinically relevant mechanism of action that may contribute to the therapeutic activity of DARA in multiple myeloma and potentially other hematological tumors.
Palavras-chave
ADCC, antibody-dependent cellular cytotoxicity; BL, Burkitt's lymphoma; BM, bone marrow; Burkitt's lymphoma; CCS, cosmic calf serum; CD38; CDC, complement-dependent cytotoxicity; DARA, daratumumab; DP, double positive; E:T, effector to target ratio; FcγR, Fc-gamma receptor; IMiD, immunomodulatory drug; MM, multiple myeloma; MNC, mononuclear cells; MÏ, macrophage; PBMC, peripheral blood mononuclear cells; daratumumab; mAb, monoclonal antibody; macrophage; multiple myeloma; phagocytosis; therapeutic antibody
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Citofagocitose
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Linfoma
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Macrófagos
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Anticorpos Monoclonais
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Anticorpos Antineoplásicos
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Mieloma Múltiplo
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article