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Using the allergic immune system to target cancer: activity of IgE antibodies specific for human CD20 and MUC1

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Abstract

Monoclonal antibodies are widely used in the treatment of many B cell lymphomas and certain solid tumors. All currently approved therapeutic monoclonal antibodies are of the immunoglobulin G (IgG) isotype. We hypothesized that tumor-specific monoclonal antibodies of the IgE isotype may serve as effective cancer therapeutics. To test this hypothesis, we produced mouse–human chimeric IgE antibodies specific for the human B cell antigen CD20 and the epithelial antigen MUC1. We demonstrate here that anti-hCD20 IgE antibodies have in vitro cytotoxic activity when used with purified allergic effector cells derived from umbilical cord blood. At an effector-tumor ratio of 2:1, mast cells and tumor-specific IgE induced a 2.5-fold increase in tumor cell death, as compared to control IgE. Similar results were observed when eosinophils were used as effector cells. In an in vivo murine model of breast carcinoma, administration of anti-hMUC1 IgE reduced the growth of MUC1+ tumors by 25–30 % in hFcεRI transgenic mice. In contrast, local production of IgE and cytokines chemotactic for macrophages, eosinophils and mast cells led to complete tumor eradication. These results suggest that allergic effector cells activated by IgE and cell surface antigens have the capacity to induce tumor cell death in vitro and in vivo. The use of chimeric antibodies and hFcεRI transgenic mice will greatly enhance investigations in the nascent field of allergo-oncology.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ANOVA:

Analysis of variance

CBEos:

Cord blood-derived eosinophils

CBMC:

Cord blood-derived mast cell

CFSE:

Carboxyfluorescein diacetate succinimidyl ester

E:T:

Effector to target ratio

FcεRI:

Fragment crystallizable epsilon receptor I

hCD20:

Human CD20

hMUC1:

Human mucin 1

hSCF:

Human stem cell factor

Ig:

Immunoglobulin

IL:

Interleukin

i.p.:

Intraperitoneal

i.v.:

Intravenous

mAb:

Monoclonal antibody

MAHA:

Mouse anti-human antibody

PBMC:

Peripheral blood mononuclear cell

PI:

Propidium iodide

SAM:

Significance analysis of microarrays

s.c.:

Subcutaneous

SCID:

Severe combined immunodeficiency

SD:

Standard deviation

TRAIL:

TNF-related apoptosis inducing ligand

TNF:

Tumor necrosis factor

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Acknowledgments

We thank J.P. Kinet from Harvard for the hFcεRI transgenic mice; H. Kita from the Mayo Clinic for helpful advice on eosinophils; O. Finn from the University of Pittsburgh for the VU-3C6 and VU-4H5 hybridomas; R. Levy from Stanford for the OCI-Ly8 lymphoma line; and Amgen, Inc. for rhSCF and rhIL6. We also thank A. Piliponsky and E. Rios from the laboratory of Stephen Galli and Y. Rosenberg-Hassan from the Stanford Human Immune Monitoring Core for helpful discussion and technical assistance; and R. Levy, S. Galli, E. Engleman and members of the Utz lab for critical review of this manuscript. P.T. was funded by the Agency for Science, Technology and Research (A*STAR) Singapore. J.M. was funded by NIH Grant CA111639-01A1 (NCI) and also supported by a generous gift from Margaret and Richard Yen. P.J.U. was the recipient of a Donald E. and Delia B. Baxter Foundation Career Development Award and was supported by the Dana Foundation, the Floren Family Trust, the Ben May Trust, NIH Grants DK61934, AI50854, AI50865, AR49328, and NHLBI Proteomics Contract HHSN288201000034C.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Pearline Zhaoying Teo, Paul J. Utz & Joseph A. Mollick

  2. Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, 875 Blake Wilbur Drive, MC 5820, Stanford, CA, 94305, USA

    Joseph A. Mollick

  3. Molecular Engineering Lab, Science and Engineering Institutes, Agency for Science, Technology and Research, Singapore, 138668, Singapore

    Pearline Zhaoying Teo

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  1. Pearline Zhaoying Teo
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Correspondence to Pearline Zhaoying Teo.

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Teo, P.Z., Utz, P.J. & Mollick, J.A. Using the allergic immune system to target cancer: activity of IgE antibodies specific for human CD20 and MUC1. Cancer Immunol Immunother 61, 2295–2309 (2012). https://doi.org/10.1007/s00262-012-1299-0

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