Cancer Immunology, Immunotherapy

, Volume 67, Issue 4, pp 605–613 | Cite as

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

  • Joseph M. Ryan
  • Payal Mittal
  • Antoine Menoret
  • Julia Svedova
  • Jeffrey S. Wasser
  • Adam J. Adler
  • Anthony T. Vella
Original Article


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.


Cancer immunotherapy Costimulation CD134 OX40 CD137 4-1BB 





Granzyme B


Methyltetrazine-PEG5-NHS ester


Trans-cyclooctene-PEG4-NHS ester


Author 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.


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).

Compliance with ethical standards

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).

Supplementary material

262_2018_2116_MOESM1_ESM.pdf (284 kb)
Supplementary material 1 (PDF 284 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Immunology, School of MedicineUConn HealthFarmingtonUSA
  2. 2.Department of Medicine, School of MedicineUConn HealthFarmingtonUSA

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