Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Guelen L

PROVIDER: S-EPMC9472132 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Guelen Lars L Fischmann Thierry O TO Wong Jerelyn J Mauze Smita S Guadagnoli Marco M Bąbała Nikolina N Wagenaars Jozef J Juan Veronica V Rosen David D Prosise Winnie W Habraken Maurice M Lodewijks Imke I Gu Danling D Stammen-Vogelzangs Judith J Yu Ying Y Baker Jeanne J Lutje Hulsik David D Driessen-Engels Lilian L Malashock Dan D Kreijtz Joost J Bertens Astrid A de Vries Evert E Bovens Astrid A Bramer Arne A Zhang Yiwei Y Wnek Richard R Troth Sean S Chartash Elliot E Dobrenkov Konstantin K Sadekova Svetlana S van Elsas Andrea A Cheung Jason K JK Fayadat-Dilman Laurence L Borst Jannie J Beebe Amy M AM Van Eenennaam Hans H

Journal for immunotherapy of cancer 20220901 9

<h4>Background</h4>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.<h4>Methods</h4>Anti-CD27 antibodies were generated and selected for agonist activity using NF-кB luciferase re ...[more]

PMID: 36100308

Similar Datasets

Project description:IntroductionCariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy.MethodsIn vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR.ResultsSimilar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine.ConclusionOverall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets