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Resistance to Immunotherapeutic Antibodies in Cancer pp 49–71Cite as

Overcoming Resistance to Therapeutic Antibodies by Targeting Fc Receptors

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Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 2))

Abstract

Monoclonal antibodies (mAb) are now at the forefront of cancer therapy. Their mechanisms of action remain the focus of intense investigation as it offers the prospect of increased potency through antibody engineering or adjuvant therapy. Although roles for complement and the induction of direct cell death remain controversial, the importance of Fc gamma receptors (FcγR) to the efficacy of therapeutic antibodies is irrefutable. However, the biology of these receptors is complex and it is now clear that in certain instances inappropriate expression or upregulation of FcγR can be detrimental. This complexity is compounded by recent exciting data showing that FcγR on both the effector and the target cell help govern therapeutic potency. In this review the ability of FcγR to elicit and modulate antibody therapy will be discussed alongside potential strategies to overcome the associated resistance.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

ADCP:

Antibody-dependent cellular phagocytosis

CDC:

Complement-dependent cytotoxicity

CLL:

Chronic lymphocytic leukaemia

CNV:

Copy number variation

DLBCL:

Diffuse large B cell lymphoma

FcγR:

Fc gamma receptor

IC:

Immune complexes

ITAM:

Immunoreceptor tyrosine-based activation motif

ITIM:

Immunoreceptor tyrosine-based inhibitory motif

mAb:

Monoclonal antibodies

MCL:

Mantle cell lymphoma

NHL:

Non Hodgkins Lymphoma

TAM:

Tumour-associated macrophages

TGF-β:

Transforming growth factor-β

TLR:

Toll-like receptor

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Acknowledgments

The authors would like to thank all of the members of the Antibody and Vaccine Group, past and present and in particular the members of the CD20 and FcγR teams. We also apologise to those authors whose work has not been cited in this review due to space limitations.

Conflict Statements:

Prof Cragg serves as a consultant for Bioinvent International and has previously served as an ad hoc consultant for Roche. MJG acts as a consultant to a number of biotech companies to write general antibody expert reports; he receives institutional payments and royalties from antibody patents and licenses. PWJ acts as a consultant to Roche and Pfizer and has received payments for lectures from Millennium Takeda and Pfizer. JCS has acted as a consultant for oxford gene technologies and received research funding from Roche.

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Authors and Affiliations

  1. Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton, MP88, Tremona Road, Southampton, SO16 6YD, UK

    Emily L. Williams, Sean H. Lim, Stephen A. Beers, Martin J. Glennie & Mark S. Cragg

  2. CR UK Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK

    Peter W. Johnson

  3. Cancer Genomics Group, Cancer Sciences Unit, University of Southampton, Southampton, UK

    Jonathan C. Strefford

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  1. Emily L. Williams
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  6. Martin J. Glennie
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  7. Mark S. Cragg
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Correspondence to Mark S. Cragg .

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  1. Molecular Genetics, University of California, Los Angeles Dept. Microbiology, Immunology &, Los Angeles, California, USA

    Benjamin Bonavida

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Williams, E.L. et al. (2013). Overcoming Resistance to Therapeutic Antibodies by Targeting Fc Receptors. In: Bonavida, B. (eds) Resistance to Immunotherapeutic Antibodies in Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 2. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7654-2_3

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