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The anti-lymphoma activities of anti-CD137 monoclonal antibodies are enhanced in FcγRIII−/− mice

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Abstract

Agonistic monoclonal antibodies (mAbs) directed against the co-signaling molecule CD137 (4-1BB) elicit potent anti-tumor immunity in mice. This anti-tumor immunity has traditionally been thought to result from the ability of the Fab portion of anti-CD137 to function as an analog for CD137L. Although binding of CD137 by anti-CD137 mAbs has the potential to cross-link the Fc fragments, enabling Fc engagement of low to moderate affinity Fc gamma receptors (FcγR), the relative import of such Fc–FcγR interactions in mediating anti-CD137 associated anti-tumor immunity is unknown. We studied the ability of a rat anti-mouse CD137 mAb (2A) to mediate the anti-tumor response against the EL4E7 lymphoma in WT and FcγR−/− strains. 2A-treated FcRγ−/− mice had improved anti-tumor immunity against EL4E7, which could be completely recapitulated in FcγRIII−/− animals. These improved anti-tumor responses were associated with increased splenic CD8β T cell and dendritic cell (DC) populations. Furthermore, there was an increase in the number of DCs expressing high levels of the CD40, CD80, and CD86 molecules that are associated with more effective antigen presentation. Our results demonstrate an unexpected inhibitory role for FcγRIII in the anti-tumor function of anti-CD137 and underscore the need to consider antibody isotype when engineering therapeutic mAbs.

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Abbreviations

2A:

Rat anti-mouse CD137 mAb

ADCC:

Antibody-dependent cellular cytotoxicity

CTLA-4:

Cytotoxic T-lymphocyte antigen 4

DC:

Dendritic cell

FcRγ:

Fc common γ-chain

FcγR:

Fc gamma receptor

GITR:

Glucocorticoid-induced TNFR-related protein

ITAM:

Immune receptor tyrosine-based activating motif

ITIM:

Immune receptor tyrosine-based inhibitory motif

MHCII:

Major histocompatibility II

mAbs:

Monoclonal antibodies

NK:

Natural killer

Tregs:

T regulatory cells

WT:

Wild type

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Acknowledgments

This work is supported by funds from the Orokawa Foundation.

Conflict of interest

Dr. Strome is a Cofounder and Major stockholder in Gliknik Inc., a biotechnology company. He also receives royalties for intellectual property, related to B7-H1 (PD-L1), licensed by the Mayo Clinic College of Medicine to third parties. All other authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, 16 South Eutaw St. Suite 500, Baltimore, MD, 21201-168, USA

    Michelle A. Sallin, Xiaoyu Zhang, Erin Burch & Scott E. Strome

  2. Department of Microbiology and Immunology, University of Maryland School of Medicine, 855 West Baltimore Street, Suite 380, HSF-I, Baltimore, MD, 21201, USA

    Edward C. So

  3. Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University Medical Center, 4000 Reservoir Road, NW, Building D-103, Washington, DC, 20057, USA

    Ling Cai

  4. College of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350003, Fujian, China

    Wei Lin

  5. Russian-American Anti-Cancer Center, Department of Physico-Chemical Biology and Biotechnology, Altai State University, 61 Lenin Street, 656049, Barnaul, Altai Territory, Russia

    Andrei I. Chapoval

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  1. Michelle A. Sallin
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Sallin, M.A., Zhang, X., So, E.C. et al. The anti-lymphoma activities of anti-CD137 monoclonal antibodies are enhanced in FcγRIII−/− mice. Cancer Immunol Immunother 63, 947–958 (2014). https://doi.org/10.1007/s00262-014-1567-2

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