Glutaminyl Cyclase Inhibitor 2

Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy

Cancer cells can evade immune surveillance through the expression of inhibitory ligands that bind their cognate receptors on immune effector cells. Expression of programmed death ligand 1 in tumor microenvironments is a major immune checkpoint for tumor-specific T cell responses as it binds to programmed cell death protein-1 on activated and dysfunctional T cells1. The activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRPα expressed on myeloid cells2-5. Using a haploid genetic screen, we here identify glutaminyl-peptide cyclotransferase-like protein (QPCTL) as a major component of the CD47-SIRPα checkpoint. Biochemical analysis demonstrates that QPCTL is critical for pyroglutamate formation on CD47 at the SIRPα binding site shortly after biosynthesis. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Furthermore, interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. These data identify QPCTL as a novel target to interfere with the CD47 pathway and thereby augment antibody therapy of cancer.

Glutaminyl Cyclase, Diseases, and Development of Glutaminyl Cyclase Inhibitors

Pyroglutamate (pE) modification, catalyzed mainly by glutaminyl cyclase (QC), is prevalent throughout nature and is particularly important in mammals including humans for the maturation of hormones, peptides, and proteins. In humans, the upregulation of QC is involved in multiple diseases and conditions including Alzheimer's disease, Huntington's disease, melanomas, thyroid carcinomas, accelerated atherosclerosis, septic arthritics, etc. This upregulation catalyzes the generation of modified mediators such as pE-amyloid beta (A?) and pE-chemokine ligand 2 (CCL2) peptides. Not surprisingly, QC has emerged as a reasonable target for the development of therapeutics to combat these diseases and conditions. In this manuscript the deleterious effects of upregulated QC resulting in disease manifestation are reviewed, along with progress on the development of QC inhibitors.

Combining daratumumab with CD47 blockade prolongs survival in preclinical models of pediatric T-ALL

Acute lymphoblastic leukemia (ALL) is the most common malignant disease affecting children. Although therapeutic strategies have improved, T-cell acute lymphoblastic leukemia (T-ALL) relapse is associated with chemoresistance and a poor prognosis. One strategy to overcome this obstacle is the application of monoclonal antibodies. Here, we show that leukemic cells from patients with T-ALL express surface CD38 and CD47, both attractive targets for antibody therapy. We therefore investigated the commercially available CD38 antibody daratumumab (Dara) in combination with a proprietary modified CD47 antibody (Hu5F9-IgG2σ) in vitro and in vivo. Compared with single treatments, this combination significantly increased in vitro antibody-dependent cellular phagocytosis in T-ALL cell lines as well as in random de novo and relapsed/refractory T-ALL patient-derived xenograft (PDX) samples. Similarly, enhanced antibody-dependent cellular phagocytosis was observed when combining Dara with pharmacologic inhibition of CD47 interactions using a glutaminyl cyclase inhibitor. Phase 2-like preclinical in vivo trials using T-ALL PDX samples in experimental minimal residual disease-like (MRD-like) and overt leukemia models revealed a high antileukemic efficacy of CD47 blockade alone. However, T-ALL xenograft mice subjected to chemotherapy first (postchemotherapy MRD) and subsequently cotreated with Dara and Hu5F9-IgG2σ displayed significantly reduced bone marrow infiltration compared with single treatments. In relapsed and highly refractory T-ALL PDX combined treatment with Dara and Hu5F9-IgG2σ was required to substantially prolong survival compared with single treatments. These findings suggest that combining CD47 blockade with Dara is a promising therapy for T-ALL, especially for relapsed/refractory disease harboring a dismal prognosis in patients.

Human glutaminyl cyclase: Structure, function, inhibitors and involvement in Alzheimer's disease

Human glutaminyl cyclase (hQC) is an important enzyme for post-translational modification by converting the N-terminal glutaminyl and glutamyl into pyroglutamate (pGlu) through cyclization. The two isoforms of hQC, secretory glutaminyl cyclase (sQC) and golgi resident glutaminyl cyclase (gQC), are involved in various pathological conditions especially in Alzheimer's disease (AD). The sQC is known to mediate the formation of pyroglutamate containing amyloid beta (pGlu-Aβ) peptides while gQC mediates the maturation of C-C motif chemokine ligand 2 (CCL2). Therefore, hQC (both sQC and gQC) inhibition is considered to be an attractive strategy to prevent the formation of pGlu-Aβ and to reduce neuroinflammation and hence provides a new opportunity for the treatment of AD. In this review, we summarize our current understanding on the structure, function and inhibitors of hQC and its involvement in Alzheimer's disease.

An overview of glutaminyl cyclase inhibitors for Alzheimer's disease

A diverse range of N-terminally truncated and modified forms of amyloid-β (Aβ) oligomers have been discovered in Alzheimer's disease brains, including the pyroglutamate-Aβ (AβpE₃). AβpE₃ species are shown to be more neurotoxic when compared with the full-length Aβ peptide. Findings visibly suggest that glutaminyl cyclase (QC) catalyzed the generation of cerebral AβpE₃, and therapeutic effects are achieved by reducing its activity. In recent years, efforts to effectively develop QC inhibitors have been pursued worldwide. The inhibitory activity of current QC inhibitors is mainly triggered by zinc-binding groups that coordinate Zn²⁺ ion in the active site and other common features. Herein, we summarized the current state of discovery and evolution of QC inhibitors as a potential Alzheimer's disease-modifying strategy.