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A new mouse expressing human Fcγ receptors to better predict therapeutic efficacy of human anti-cancer antibodies

Leukemia volume 32, pages 547–549 (2018)Cite this article

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The mechanisms of action of cytotoxic monoclonal antibodies (mAbs) include direct effects via agonistic or antagonistic binding, and FcγR-dependent mechanisms to induce antibody-dependent cell cytotoxicity (ADCC). FcγR engagement has been shown to be the critical determinant of mAb therapeutic efficacy in humans.1, 2 An antibody’s Fc domain’s relative affinity for the activating and inhibitory FcγR, called the A/I ratio, can determine its functional output,3 and is directly correlated to therapeutic efficacy in vivo.4 This has spawned recent efforts to engineer antibodies with enhanced activating FcγR affinity.

Only 14% of promising mAb therapies prove effective in patients and most do not make it to the market, despite strong preclinical efficacy in vivo.5 Anti-cancer antibodies are even less successful than those for other indications. This problem calls for better predictive models that can more efficiently determine whether an antibody will succeed in the clinic.

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Acknowledgements

Dr Michael Kharas provided the Hemavet machine and Dr Joseph Sun supplied the anti-NK1.1 (PK136) antibody. Dr Dmitry Pankov, Dr Katja Behling and Aaron Chang assisted with mouse work. The work was supported by: a Ruth L Kirschstein National Research Service Award (F31 CA189305 to EC), NIH R01 CA55349, P01 CA33049, CCSG P30-008749 to DAS, The Tudor Fund, Lymphoma Foundation and The Center for Experimental Therapeutics to DAS; American Foundation for AIDS Research Mathilde Krim Fellowship in Basic Biomedical Research (109519-60-RKVA) to SB, and the NIH P01 CA190174 and R35 CA196620 to JVR. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author contributions

EC conceived and performed mouse breeding and colony maintenance, flow cytometry characterization of new mice strains, ITP model experiments, lymphoma antibody therapy experiments and authored the manuscript. SB contributed to the conception of breeding scheme and experimental plans, contributed mice and antibody resources, performed the antibody-FcγR SPR analysis, and contributed methods and edited the manuscript. GM and PM contributed to mouse characterization experiments and edited the manuscript. KST performed statistical analysis, contributed to the methods and edited the manuscript. JVR contributed mice and other resources and edited the manuscript. DAS contributed resources and helped guide the planning and execution of the experiments and edited the manuscript.

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Authors and Affiliations

  1. Gerstner Sloan Kettering Graduate School, Memorial Sloan Kettering, New York, NY, USA

    E Casey & D A Scheinberg

  2. Molecular Pharmacology Program, Memorial Sloan Kettering, New York, NY, USA

    E Casey, G Mo, P Mondello & D A Scheinberg

  3. Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY, USA

    S Bournazos & J V Ravetch

  4. Epidemiology & Biostatistics, Memorial Sloan Kettering, New York, NY, USA

    K S Tan

  5. Weill Cornell Medicine, New York, NY, USA

    D A Scheinberg

Authors
  1. E Casey
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  2. S Bournazos
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  4. P Mondello
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  6. J V Ravetch
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  7. D A Scheinberg
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Corresponding author

Correspondence to D A Scheinberg.

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Competing interests

A patent has been filed by MSKCC encompassing these novel mouse strains. The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Casey, E., Bournazos, S., Mo, G. et al. A new mouse expressing human Fcγ receptors to better predict therapeutic efficacy of human anti-cancer antibodies. Leukemia 32, 547–549 (2018). https://doi.org/10.1038/leu.2017.293

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