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A novel biologic platform elicits profound T cell costimulatory activity and antitumor immunity in mice

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Abstract

Combination immunotherapies utilizing complementary modalities that target distinct tumor attributes or immunosuppressive mechanisms, or engage different arms of the antitumor immune response, can elicit greater therapeutic efficacy than the component monotherapies. Increasing the number of agents included in a therapeutic cocktail can further increase efficacy, however, this approach poses numerous challenges for clinical translation. Here, a novel platform to simplify combination immunotherapy by covalently linking immunotherapeutic agonists to the costimulatory receptors CD134 and CD137 into a single heterodimeric drug, “OrthomAb”, is shown. This reagent not only retains costimulatory T cell activity, but also elicits unique T cell functions that are not programmed by either individual agonist, and preferentially expands effector T cells over Tregs. Finally, in an aggressive melanoma model OrthomAb elicits better therapeutic efficacy compared to the unlinked agonists. This demonstration that two drugs can be combined into one provides a framework for distilling complex combination drug cocktails into simpler delivery platforms.

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Abbreviations

Eomes:

Eomesodermin

GzmB:

Granzyme B

MTz:

Methyltetrazine-PEG5-NHS ester

TCO:

Trans-cyclooctene-PEG4-NHS ester

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Funding

This work was supported by National Institutes of Health Grants R01CA109339 and R01AI094640 as well as a SPARK Award from UConn Health (to Adam J. Adler and Anthony T. Vella).

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Authors and Affiliations

  1. Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA

    Joseph M. Ryan, Payal Mittal, Antoine Menoret, Julia Svedova, Adam J. Adler & Anthony T. Vella

  2. Department of Medicine, School of Medicine, UConn Health, Farmington, CT, 06030, USA

    Jeffrey S. Wasser

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  1. Joseph M. Ryan
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  2. Payal Mittal
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  3. Antoine Menoret
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Contributions

ATV, AJA and JMR were involved in the study conception and design. JMR, AJA, PM, AM and JS were involved in data acquisition and analysis. AJA, ATV and JMR drafted the manuscript. All authors contributed intellectually during the course of the research as well as in critical revision of the manuscript.

Corresponding authors

Correspondence to Adam J. Adler or Anthony T. Vella.

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Conflict of interest

Adam J. Adler and Anthony T. Vella have filed a patent application on OrthomAb. All other authors declare that they have no conflict of interest.

Ethical approval

All experiments involving mice were conducted in accordance with the ethical standards established by the National Institutes of Health and UConn Health, and were approved by the UConn Health Institutional Animal Care and Use Committee (IACUC).

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Ryan, J.M., Mittal, P., Menoret, A. et al. A novel biologic platform elicits profound T cell costimulatory activity and antitumor immunity in mice. Cancer Immunol Immunother 67, 605–613 (2018). https://doi.org/10.1007/s00262-018-2116-1

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