Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells

Maria C Ochoa; Elisabeth Perez-Ruiz; Luna Minute; Carmen Oñate; Guiomar Perez; Inmaculada Rodriguez; Aintzane Zabaleta; Diego Alignani; Myriam Fernandez-Sendin; Ascension Lopez; Aura Muntasell; Miguel F Sanmamed; Bruno Paiva; Miguel Lopez-Botet; Pedro Berraondo; Ignacio Melero

doi:10.1080/2162402X.2019.1599636

Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells

Oncoimmunology. 2019 Apr 13;8(7):1599636. doi: 10.1080/2162402X.2019.1599636. eCollection 2019.

Authors

Maria C Ochoa^{1

2

3

4}, Elisabeth Perez-Ruiz⁵, Luna Minute^{1

2

3

4}, Carmen Oñate^{2

3}, Guiomar Perez^{2

3}, Inmaculada Rodriguez^{2

3}, Aintzane Zabaleta^{1

2

4

6}, Diego Alignani^{2

4

6}, Myriam Fernandez-Sendin^{1

2}, Ascension Lopez^{2

3

7}, Aura Muntasell⁸, Miguel F Sanmamed^{1

2

3}, Bruno Paiva^{1

2

4

6}, Miguel Lopez-Botet^{8

9}, Pedro Berraondo^{1

2

4}, Ignacio Melero^{1

2

3

4}

Affiliations

¹ Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.
² Navarra Institute for Health Research (IDISNA), Pamplona, Spain.
³ Department of Immunology and Immunotherapy, University Hospital of Navarra, Pamplona, Spain.
⁴ Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁵ Department of Medical Oncology, Hospital Costa del Sol, Marbella, Spain.
⁶ Cytometry Unit, Center for Applied Medical Research (CIMA), Pamplona, Spain.
⁷ Cell Therapy Area, University Hospital of Navarra, Pamplona, Spain.
⁸ Immunity and Infection Lab, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
⁹ Departament de Ciències Experimentals i de la Salut. Immunology Unit, University Pompeu Fabra, Barcelona, Spain.

Abstract

Daratumumab is an anti-CD38 fully human IgG1 mAb approved for multiple myeloma treatment. One of the proposed mechanisms of action is the induction of antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells. NK cells acquire surface CD137 expression in the presence of solid-phase-attached daratumumab and when encountering a daratumumab-coated CD38⁺ tumor cell line. In this setting, addition of the agonist anti-CD137 mAb urelumab enhances NK-cell activation increasing CD25 expression and IFNɣ production. However, in vitro ADCC is not increased by the addition of urelumab both in 4h or 24h lasting experiments. To study urelumab-increased daratumumab-mediated ADCC activity in vivo, we set up a mouse model based on the intravenous administration of a luciferase-transfected multiple myeloma cell line of human origin, human NK cells and daratumumab to immuno-deficient NSG mice. In this model, intravenous administration of urelumab 24h after daratumumab delayed tumor growth and prolonged mice survival.

Keywords: ADCC; CD137; NK cells; daratumumab; multiple myeloma.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

This work was supported by Asociación Española contra el Cancer (Fundación AECC), Foundation for Applied Medical Research (FIMA), Worldwide Cancer Research (AIRC) and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional (FEDER) under Grant [PI16/00668]. This project has received funding from the European Union´s Horizon 2020 research and innovation programme (grant agreement [n° 635122 – PROCROP]. P.B. was supported by a Miguel Servet II [CPII15/00004] contract from Instituto de Salud Carlos III;