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Efficacy and mechanism of the anti-CD38 monoclonal antibody Daratumumab against primary effusion lymphoma

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Abstract

Primary effusion lymphoma (PEL) is a rare, aggressive B cell non-Hodgkin’s lymphoma of the body cavities with malignant effusions. The prognosis is poor, and no optimal treatment has been established. CD38 is a type II transmembrane glycoprotein known to overexpress in multiple myeloma (MM). Daratumumab (DARA), a human CD38-targeting monoclonal antibody (mAb), is approved for MM treatment. In this study, we found expression of CD38 on PEL cells and assessed the anti-PEL activity of DARA. We found that both KHYG-1 and N6 (CD16-transfected KHYG-1) NK cell lines showed direct killing activity against PEL cells with induction of CD107a, and NK-mediated cytotoxicity by N6NK (CD16+) cells increased with DARA treatment. We confirmed direct NK activity and antibody-dependent cell cytotoxicity (ADCC) by expanded NK cells, indicating that DARA has high ADCC activity. We elucidated the antibody-dependent cell phagocytosis (ADCP) by using human monocyte-derived macrophages (MDMs) and mouse peritoneal macrophages. DARA also showed potent complement-dependent cytolysis (CDC) toward PEL. DARA also induced PEL cell death in the presence of a cross-linking antibody. Moreover, treatment with DARA inhibited tumor growth in a PEL xenograft mouse model. These results provide preclinical evidence that Ab targeting of CD38 could be an effective therapeutic strategy for the treatment of PEL.

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Abbreviations

ADCC:

Antibody-dependent cell cytotoxicity

ADCP:

Antibody-dependent cell phagocytosis

CDC:

Complement-dependent cytolysis

DARA:

Daratumumab

MM:

Multiple myeloma

MDMs:

Human monocyte-derived macrophages

NHL:

Non-Hodgkin’s lymphoma

PEL:

Primary effusion lymphoma

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Acknowledgements

We are grateful to Ms. Sawako Fujikawa for technical assistance and Ms. Michiko Teramoto for secretarial assistance.

Funding

This work was supported in part by the Research Program on HIV/AIDS (Grant No. 18fk0410008h003) of the Japan Agency for Medical Research and Development and Grants-in-Aid for Science Research (16K08742) from the Ministry of Education, Science, Sports, and Culture of Japan.

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  1. Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan

    Jutatip Panaampon, Ryusho Kariya & Seiji Okada

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  1. Jutatip Panaampon
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JP contributed to conceptualization, methodology, formal analysis, investigation, and writing—original draft; RK contributed to investigation and methodology; and SO contributed to conceptualization, resources, writing—review and editing, supervision, project administration, and funding acquisition.

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Correspondence to Seiji Okada.

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Mice were bred and cared for in the animal research facility according to institutional guidelines. All experimental procedures in this study were approved by the Institutional Animal Care and Use Committee at Kumamoto University, Japan.

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Panaampon, J., Kariya, R. & Okada, S. Efficacy and mechanism of the anti-CD38 monoclonal antibody Daratumumab against primary effusion lymphoma. Cancer Immunol Immunother 71, 1017–1031 (2022). https://doi.org/10.1007/s00262-021-03054-8

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