PT - JOURNAL ARTICLE AU - Guelen, Lars AU - Fischmann, Thierry O AU - Wong, Jerelyn AU - Mauze, Smita AU - Guadagnoli, Marco AU - Bąbała, Nikolina AU - Wagenaars, Jozef AU - Juan, Veronica AU - Rosen, David AU - Prosise, Winnie AU - Habraken, Maurice AU - Lodewijks, Imke AU - Gu, Danling AU - Stammen-Vogelzangs, Judith AU - Yu, Ying AU - Baker, Jeanne AU - Lutje Hulsik, David AU - Driessen-Engels, Lilian AU - Malashock, Dan AU - Kreijtz, Joost AU - Bertens, Astrid AU - de Vries, Evert AU - Bovens, Astrid AU - Bramer, Arne AU - Zhang, Yiwei AU - Wnek, Richard AU - Troth, Sean AU - Chartash, Elliot AU - Dobrenkov, Konstantin AU - Sadekova, Svetlana AU - van Elsas, Andrea AU - Cheung, Jason K AU - Fayadat-Dilman, Laurence AU - Borst, Jannie AU - Beebe, Amy M AU - Van Eenennaam, Hans TI - Preclinical characterization and clinical translation of pharmacodynamic markers for MK-5890: a human CD27 activating antibody for cancer immunotherapy AID - 10.1136/jitc-2022-005049 DP - 2022 Sep 01 TA - Journal for ImmunoTherapy of Cancer PG - e005049 VI - 10 IP - 9 4099 - http://jitc.bmj.com/content/10/9/e005049.short 4100 - http://jitc.bmj.com/content/10/9/e005049.full SO - J Immunother Cancer2022 Sep 01; 10 AB - Background Immune checkpoint inhibitors (ICI) have radically changed cancer therapy, but most patients with cancer are unresponsive or relapse after treatment. MK-5890 is a CD27 agonist antibody intended to complement ICI therapy. CD27 is a member of the tumor necrosis factor receptor superfamily that plays a critical role in promoting responses of T cells, B cells and NK cells.Methods Anti-CD27 antibodies were generated and selected for agonist activity using NF-кB luciferase reporter assays. Antibodies were humanized and characterized for agonism using in vitro T-cell proliferation assays. The epitope recognized on CD27 by MK-5890 was established by X-ray crystallography. Anti-tumor activity was evaluated in a human CD27 knock-in mouse. Preclinical safety was tested in rhesus monkeys. Pharmacodynamic properties were examined in mouse, rhesus monkeys and a phase 1 dose escalation clinical study in patients with cancer.Results Humanized anti-CD27 antibody MK-5890 (hIgG1) was shown to bind human CD27 on the cell surface with sub-nanomolar potency and to partially block binding to its ligand, CD70. Crystallization studies revealed that MK-5890 binds to a unique epitope in the cysteine-rich domain 1 (CRD1). MK-5890 activated CD27 expressed on 293T NF-κB luciferase reporter cells and, conditional on CD3 stimulation, in purified CD8+ T cells without the requirement of crosslinking. Functional Fc-receptor interaction was required to activate CD8+ T cells in an ex vivo tumor explant system and to induce antitumor efficacy in syngeneic murine subcutaneous tumor models. MK-5890 had monotherapy efficacy in these models and enhanced efficacy of PD-1 blockade. MK-5890 reduced in an isotype-dependent and dose-dependent manner circulating, but not tumor-infiltrating T-cell numbers in these mouse models. In rhesus monkey and human patients, reduction in circulating T cells was transient and less pronounced than in mouse. MK-5890 induced transient elevation of chemokines MCP-1, MIP-1α, and MIP-1β in the serum of mice, rhesus monkeys and patients with cancer. MK-5890 was well tolerated in rhesus monkeys and systemic exposure to MK-5890 was associated with CD27 occupancy at all doses.Conclusions MK-5890 is a novel CD27 agonistic antibody with the potential to complement the activity of PD-1 checkpoint inhibition in cancer immunotherapy and is currently undergoing clinical evaluation.Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. X-ray crystal structure factors and coordinates files have been deposited for public access in the Protein Data Bank (PDB, http://www.rcsb.org) under the code 8DS5.