RT Journal Article
SR Electronic
T1 Preclinical characterization and clinical translation of pharmacodynamic markers for MK-5890: a human CD27 activating antibody for cancer immunotherapy
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e005049
DO 10.1136/jitc-2022-005049
VO 10
IS 9
A1 Lars Guelen
A1 Thierry O Fischmann
A1 Jerelyn Wong
A1 Smita Mauze
A1 Marco Guadagnoli
A1 Nikolina Bąbała
A1 Jozef Wagenaars
A1 Veronica Juan
A1 David Rosen
A1 Winnie Prosise
A1 Maurice Habraken
A1 Imke Lodewijks
A1 Danling Gu
A1 Judith Stammen-Vogelzangs
A1 Ying Yu
A1 Jeanne Baker
A1 David Lutje Hulsik
A1 Lilian Driessen-Engels
A1 Dan Malashock
A1 Joost Kreijtz
A1 Astrid Bertens
A1 Evert de Vries
A1 Astrid Bovens
A1 Arne Bramer
A1 Yiwei Zhang
A1 Richard Wnek
A1 Sean Troth
A1 Elliot Chartash
A1 Konstantin Dobrenkov
A1 Svetlana Sadekova
A1 Andrea van Elsas
A1 Jason K Cheung
A1 Laurence Fayadat-Dilman
A1 Jannie Borst
A1 Amy M Beebe
A1 Hans Van Eenennaam
YR 2022
UL http://jitc.bmj.com/content/10/9/e005049.abstract
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.