Preclinical characterization and clinical translation of pharmacodynamic markers for MK-5890: a human CD27 activating antibody for cancer immunotherapy

Abstract

BackgroundImmune 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.MethodsAnti-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.ResultsHumanized 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.ConclusionsMK-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.

Fcγ receptor binding is required for maximal immunostimulation by CD70-Fc

“…The overarching aim of the current study was to develop a potent CD27 agonist suitable for in vivo application. Current efforts to develop agonist antibodies targeting CD27 as well as other members of TNFRSF have been fraught with difficulties due to the vastly different immunostimulatory activities displayed by agents targeting the same receptor ( 21 , 22 , 40 ). Agonism is known to correlate with the ability of antibodies to induce receptor clustering, an attribute that is affected by epitope, antibody hinge flexibility, interaction with FcγRs, and affinity ( 18 , 21 , 36 , 40 – 42 ).…”

“…However, there is no consensus on which of these agents represent the therapeutic of choice for delivering optimal CD27 costimulation. A wide range of agonistic activity has been reported for different anti-CD27 mAbs ( 21 , 22 ). Furthermore, the activity of anti-CD27 mAbs may depend on antibody isotype which affects binding to the inhibitory and activatory Fcγ receptors (FcγRs) ( 18 , 21 ).…”

Delivering co-stimulatory tumor necrosis factor receptor agonism for cancer immunotherapy: past, current and future perspectives

“…Another CD27 targeting agonistic mAb in development is MK-5890, which is a humanized IgG1 antibody that is being tested in the clinic as a single agent or in combination with PD-1 blocking agents in advanced solid tumors. The pre-clinical characterization of the mAb demonstrated that it could induce anti-tumor responses as a monotherapy or in combination with PD-1 blockade ( 120 ). Early results suggest an acceptable safety profile, although 24% of patients in the monotherapy group developed grade 3 or 4 adverse events related to treatment.…”

“…Early signs of efficacy with MK-5890 monotherapy or combination, stimulating anti-tumor responses in patients, were observed ( 121 ). Although the mAb could induce transient upregulation of chemokine levels in patients, it also induced decreases in the level of circulating T cells ( 120 ) suggesting that identifying the right dosing regimen will be important for the successful application of this mAb. A recent study in a pre-clinical setting addressed the determinants of agonism for anti-CD27 mAb ( 112 ).…”

Humanized mouse models: A valuable platform for preclinical evaluation of human cancer

“…Similarly, injecting recombinant ES cells successly carrying human CD27 led to the generation of chimeric mice. Then, utilizing Flp‐mediated recombination, the mice carrying the neomycin (NEO) sequence were bred with OZFlp deleter mice to eliminate NEO (Guelen et al, 2022). This method offered the benefit of precision foreign gene injection into ES cells, which is suitable for many complex genes.…”