Enhancing natural killer cell-mediated lysis of lymphoma cells by combining therapeutic antibodies with CD20-specific immunoligands engaging NKG2D or NKp30.

Abstract:

:Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated through the IgG Fc receptor FcγRIIIa represents a major effector function of many therapeutic antibodies. In an attempt to further enhance natural killer (NK) cell-mediated ADCC, we combined therapeutic antibodies against CD20 and CD38 with recombinant immunoligands against the stimulatory NK cell receptors NKG2D or NKp30. These immunoligands, respectively designated as ULBP2:7D8 and B7-H6:7D8, contained the CD20 scFv 7D8 as a targeting moiety and a cognate ligand for either NKG2D or NKp30 (i.e. ULBP2 and B7-H6, respectively). Both the immunoligands synergistically augmented ADCC in combination with the CD20 antibody rituximab and the CD38 antibody daratumumab. Combinations with ULBP2:7D8 resulted in higher cytotoxicity compared to combinations with B7-H6:7D8, suggesting that coligation of FcγRIIIa with NKG2D triggered NK cells more efficiently than with NKp30. Addition of B7-H6:7D8 to ULBP2:7D8 and rituximab in a triple combination did not further increase the extent of tumor cell lysis. Importantly, immunoligand-mediated enhancement of ADCC was also observed for tumor cells and autologous NK cells from patients with hematologic malignancies, in which, again, ULBP2:7D8 was particularly active. In summary, co-targeting of NKG2D was more effective in promoting rituximab or daratumumab-mediated ADCC by NK cells than co-ligation of NKp30. The observed increase in the ADCC activity of these therapeutic antibodies suggests promise for a 'dual-dual-targeting' approach in which tumor cell surface antigens are targeted in concert with two distinct activating NK cell receptors (i.e. FcγRIIIa and NKG2D or B7-H6).

journal_name

Oncoimmunology

journal_title

Oncoimmunology

authors

Kellner C,Günther A,Humpe A,Repp R,Klausz K,Derer S,Valerius T,Ritgen M,Brüggemann M,van de Winkel JG,Parren PW,Kneba M,Gramatzki M,Peipp M

doi

10.1080/2162402X.2015.1058459

subject

Has Abstract

pub_date

2015-06-05 00:00:00

pages

e1058459

issue

1

eissn

2162-4011

issn

2162-402X

pii

1058459

journal_volume

5

pub_type

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