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Ab-IL2 fusion proteins mediate NK cell immune synapse formation by polarizing CD25 to the target cell-effector cell interface

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Abstract

The huKS-IL2 immunocytokine (IC) consists of IL2 fused to a mAb against EpCAM, while the hu14.18-IL2 IC recognizes the GD2 disialoganglioside. They are under evaluation for treatment of EpCAM+ (ovarian) and GD2+ (neuroblastoma and melanoma) malignancies because of their proven ability to enhance tumor cell killing by antibody-dependent cell-mediated cytotoxicity (ADCC) and by antitumor cytotoxic T cells. Here, we demonstrate that huKS-IL2 and hu14.18-IL2 bind to tumor cells via their antibody components and increase adhesion and activating immune synapse (AIS) formation with NK cells by engaging the immune cells’ IL-2 receptors (IL2R). The NK leukemia cell line, NKL (which expresses high affinity IL2Rs), shows fivefold increase in binding to tumor targets when treated with IC compared to matching controls. This increase in binding is effectively inhibited by blocking antibodies against CD25, the α-chain of the IL2R. NK cells isolated from the peritoneal environment of ovarian cancer patients, known to be impaired in mediating ADCC, bind to huKS-IL2 via CD25. The increased binding between tumor and effector cells via ICs is due to the formation of AIS that are characterized by the simultaneous polarization of LFA-1, CD2 and F-actin at the cellular interface. AIS formation of peritoneal NK and NKL cells is inhibited by anti-CD25 blocking antibody and is 50–200% higher with IC versus the parent antibody. These findings demonstrate that the IL-2 component of the IC allows IL2Rs to function not only as receptors for this cytokine but also as facilitators of peritoneal NK cell binding to IC-coated tumor cells.

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Acknowledgments

Funding for this research was provided by grants from the Department of Defense (#W81XWH-04-1-0102), Ovarian Cancer Research Fund (UW/UWM.05), start-up funds from the Department of Obstetrics and Gynecology to MSP, a charitable donation from Jean McKenzie to JC and MSP, a T32 training grant to JAAG, and by U10CA98543 COG Group Chair Grant, and R01-CA-32685-25, P30-CA14520, CA87025, CA81403, RR03186, and grants from the Midwest Athletes for Childhood Cancer Fund, The Crawdaddy Foundation, The St. Baldrick’s Foundation, The Evan Dunbar Foundation and Abbie’s Fund to PMS. We are deeply grateful to Kathy Schell for her advice and help and acknowledge the support provided by the University of Wisconsin Comprehensive Cancer Centers Flow Cytometry facility which is supported by a core grant (CA14520) from the National Institutes of Health, to Lance Rodenkirk for help with confocal microscopy and image analysis, and to Lori Scardino for help with the schematic figure.

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  1. Jennifer A. A. Gubbels

    Present address: Department of Biology, Augustana College, Sioux Falls, SD, 57197, USA

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, 53711, USA

    Jennifer A. A. Gubbels, Sachi Horibata, Arvinder K. Kapur, Dhara Patel, Manish S. Patankar & Joseph Connor

  2. Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, 53711, USA

    Brian Gadbaw & Paul M. Sondel

  3. Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, 53711, USA

    Ilia N. Buhtoiarov, Jacquelyn A. Hank & Paul M. Sondel

  4. Provenance Biopharmaceuticals Corp., Waltham, MA, USA

    Stephen D. Gillies

  5. 4159 Wisconsin Institutes for Medical Research, 1111 Highland Ave, Madison, WI, 53705, USA

    Paul M. Sondel

  6. H4/657 CSC, 600 Highland Avenue, Madison, WI, 53792-6188, USA

    Manish S. Patankar

  7. Clinical Science Center-H4/650, 600 Highland Ave, Box 6188, Madison, WI, 53792, USA

    Joseph Connor

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  1. Jennifer A. A. Gubbels
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Correspondence to Jennifer A. A. Gubbels, Paul M. Sondel, Manish S. Patankar or Joseph Connor.

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262_2011_1072_MOESM1_ESM.ppt

Supplemental File 1. This figure shows the schematic relationships of GD2 distribution on M21 tumor cells, IL2R on NKL cells and the localization of FITC-conjugated hu14.18-IL2 to these M21 and NKL cells, when cultured alone, or when synapses are formed via the IC, based on the actual photomicrographs shown in Figs. 6 and 7 (PPT 301 kb)

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Gubbels, J.A.A., Gadbaw, B., Buhtoiarov, I.N. et al. Ab-IL2 fusion proteins mediate NK cell immune synapse formation by polarizing CD25 to the target cell-effector cell interface. Cancer Immunol Immunother 60, 1789–1800 (2011). https://doi.org/10.1007/s00262-011-1072-9

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