An Fc-optimized NKG2D-immunoglobulin G fusion protein for induction of natural killer cell reactivity against leukemia

作者：Steinbacher Julia; Baltz Ghahremanpour Katrin; Schmiedel Benjamin Joachim; Steinle Alexander; Jung Gundram; Kuebler Ayline; Andre Maya Caroline; Grosse Hovest Ludger; Salih Helmut Rainer^*

来源：International Journal of Cancer, 2015, 136(5): 1073-1084.

DOI：10.1002/ijc.29083

• leukemia
• NK cells
• NKG2D ligands
• ADCC

Recruitment of Fc-receptor-bearing effector cells, such as natural killer (NK) cells, is a feature critical for the therapeutic success of antitumor antibodies and can be improved by the modifications of an antibody's Fc part. The various ligands of the activating immunoreceptor NKG2D, NKG2DL) are selectively expressed on malignant cells including leukemia. We here took advantage of the tumor-associated expression of NKG2DL for targeting leukemic cells by NKG2D-immunoglobulin G (IgG)1 fusion proteins containing modified Fc parts. Compared to NKG2D-Fc containing a wild-type Fc part (NKG2D-Fc-WT), our mutants (S239D/I332E and E233P/L234V/L235A/G236/A327G/A330S) displayed highly enhanced (NKG2D-Fc-ADCC) and abrogated (NKG2D-Fc-KO) affinity to the NK cell Fc receptor, respectively. Functional analyses with allogenic as well as autologous NK cells and primary malignant cells of leukemia patients revealed that NKG2D-Fc-KO significantly reduced NK reactivity by blocking immunostimulatory NKG2D-NKG2DL interaction. NKG2D-Fc-WT already enhanced antileukemia reactivity by inducing antibody-dependent cellular cytotoxicity (ADCC) with NKG2D-Fc-ADCC mediating significantly stronger effects. Parallel application of NKG2D-Fc-ADCC with Rituximab caused additive effects in lymphoid leukemia. In line with the tumor-associated expression of NKG2DL, no NK cell ADCC against resting healthy blood cells was induced. Thus, NKG2D-Fc-ADCC potently enhances NK antileukemia reactivity despite the inevitable reduction of activating signals upon binding to NKG2DL and may constitute an attractive means for immunotherapy of leukemia.
What's new? If antibodies could be engineered to recognize molecules that are common to many types of cancer, it could lead to new therapies. And if those antibodies could be modified so that they recruit and activate more immune cells, it could make immunotherapy far more effective. In this study, the authors developed a modified antibody-fusion protein that strongly binds to different types of NKG2DL, a class of molecules expressed by many different tumor types. This binding, in turn, activated NK cells against leukemia cellsincluding myeloid types, for which no antibody-based immunotherapy is yet available.

• 出版日期2015-3-1