The Choice between Intravenous and Subcutaneous Immunoglobulins: Aspects for Consideration.

BACKGROUND: Intravenous immunoglobulin and subcutaneous immunoglobulin preparations are used to treat primary and secondary immunodeficiencies, as well as autoimmune and inflammatory conditions. SUMMARY: For certain indications, only defined formulations or routes of administration are approved by health authorities. However, for other diseases, there are more options, and treatment decisions may be based on different aspects, such as patient conditions and preferences, pharmacokinetics, or pharmacoeconomic considerations. KEY MESSAGES: Understanding the two different treatment modalities may support the decision-making for the optimal therapeutic option for individual patients. This review summarizes the latest insights into the direct and indirect comparison between the two types of products.

Sensitivity of human meningioma cells to the cyclin-dependent kinase inhibitor, TG02.

Standards of care for meningioma include surgical resection and radiotherapy whereas pharmacotherapy plays almost no role in this disease. We generated primary cultures from surgically removed meningiomas to explore the activity of a novel cyclin-dependent kinase inhibitor, TG02, in meningioma cell cultures. Tumor and cell cultures were characterized by mutation profiling and DNA methylation profiling. DNA methylation data were used to allot each sample to one out of six previously established meningioma methylation classes: benign (ben)-1, 2, 3, intermediate (int)-A, B, and malignant (mal). Four tumors assigned to the methylation class ben-2 showed the same class in culture whereas cultures from five non-ben-2 tumors showed a more malignant class in four patients. Cell cultures were uniformly sensitive to TG02 in the nanomolar range. Assignment of the cell cultures to a more malignant methylation class appeared to be more closely associated with TG02 sensitivity than assignment to a higher WHO grade of the primary tumors. Primary cell cultures from meningioma facilitate the investigation of the anti-meningioma activity of novel agents. TG02, an orally available cyclin-dependent kinase (CDK) inhibitor, warrants further exploration.

Depatuxizumab Mafodotin (ABT-414)-induced Glioblastoma Cell Death Requires EGFR Overexpression, but not EGFRY1068 Phosphorylation.

Glioblastomas commonly (40%) exhibit epidermal growth factor receptor (EGFR) amplification; half of these tumors carry the EGFRvIII deletion variant characterized by an in-frame deletion of exons 2-7, resulting in constitutive EGFR activation. Although EGFR tyrosine kinase inhibitors had only modest effects in glioblastoma, novel therapeutic agents targeting amplified EGFR or EGFRvIII continue to be developed.Depatuxizumab mafodotin (ABT-414) is an EGFR-targeting antibody-drug conjugate consisting of the mAb 806 and a toxic payload, monomethyl auristatin F. Because glioma cell lines and patient-derived glioma-initiating cell models expressed too little EGFR in vitro to be ABT-414-sensitive, we generated glioma sublines overexpressing EGFR or EGFRvIII to explore determinants of ABT-414-induced cell death.Overexpression of EGFRvIII induces sensitization to ABT-414 more readily than overexpression of EGFR in vitro and in vivo Exposure to ABT-414 in vivo eliminated EGFRvIII-expressing tumor cells, and recurrent tumors were devoid of EGFRvIII expression. There is no bystander killing of cells devoid of EGFR expression. Surprisingly, either exposure to EGF or to EGFR tyrosin kinase inhibitors reduce EGFR protein levels and are thus not strategies to promote ABT-414-induced cell killing. Furthermore, glioma cells overexpressing kinase-dead EGFR or EGFRvIII retain binding of mAb 806 and sensitivity to ABT-414, allowing to dissociate EGFR phosphorylation from the emergence of the "active" EGFR conformation required for ABT-414 binding.The combination of EGFR-targeting antibody-drug conjugates with EGFR tyrosine kinase inhibitors carries a high risk of failure. Promoting EGFR expression rather than phosphorylation should result in glioblastoma cell sensitization to ABT-414.

Synergistic growth inhibition mediated by dual PI3K/mTOR pathway targeting and genetic or direct pharmacological AKT inhibition in human glioblastoma models.

Molecular genetic aberrations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway are common in human cancers including glioblastoma, yet, novel therapeutic approaches targeting this pathway in glioblastoma have not been successful. We hypothesized that molecular profiling in combination with in vitro drug sensitivity testing allows to identify signatures associated with sensitivity or resistance to PI3K/mTOR pathway inhibition. We analyzed the molecular mechanisms determining sensitivity to PI3K/mTOR inhibition using gene silencing or pharmacological target inhibition and proliferation, clonogenicity, or spherogenicity as readouts, in human long-term glioma cell (LTC) lines and glioma-initiating cells (GIC). Cultured glioma cells were universally sensitive to growth inhibition induced by PQR309, a novel, dual pan-PI3K/mTOR antagonist. Cells exhibited profound growth arrest, but little apoptotic or necrotic cell death as confirmed by electron microscopy; yet, there was evidence of senescence. Cell lines with high basal levels of phosphorylated (active) AKT, low levels of phosphorylated (inactive) protein translation repressor eukaryotic initiation factor (eIF) 4E-binding protein 1 (p4E-BP1), and high levels of Ser9-phosphorylated (inactive) glycogen synthase kinase 3 beta (pGSK3ß) were more sensitive to PQR309. Accordingly, the activity of PQR309 was synergistically enhanced by AKT gene silencing or direct pharmacological AKT inhibition. In vivo studies confirmed the anti-glioma activity of PQR309 alone or in combination with AKT inhibition in the orthotopic LN-229 glioma xenograft model in nude mice. These data justify to explore combined targeted therapy approaches in glioblastoma that aim at down-regulating AKT function to enhance the therapeutic potential of dual PI3K/mTOR inhibitors.

Profound, durable and MGMT-independent sensitivity of glioblastoma cells to cyclin-dependent kinase inhibition.

TG02 is a novel cyclin-dependent kinase (CDK) inhibitor and thought to act mainly via CDK-9 inhibition-dependent depletion of short-lived oncoproteins such as MCL-1 or c-MYC. We studied the activity of TG02 in 9 human long-term glioma cell lines (LTC) and 5 glioma-initiating cell lines (GIC) using various cell death assays in vitro and in the LN-229 LTC and ZH-161 GIC models in vivo. TG02 exhibits strong anti-tumor cell activity with EC50 concentrations in the nanomolar range. Median survival in the LN-229 and ZH-161 models was moderately prolonged by TG02. Neither constitutive CDK levels nor those of MCL-1 or c-MYC correlated with sensitivity to TG02. Cdk-9 or cdk-5 gene silencing alone did not fully reproduce the effects of TG02. C-myc gene silencing inhibited cell growth, but did not modulate TG02 activity. Electron microscopy revealed cell death to be essentially apoptotic. High concentrations of TG02 induced annexin V binding and minor caspase 3 cleavage, but the pan-caspase inhibitor, zVAD-fmk, or BCL-2 or MCL-1 gene transfer only moderately attenuated TG02-induced cell death, and caspase inhibition did not prevent loss of MCL-1 or c-MYC. TG02 activity was independent of O6 -methylguanine DNA methyltransferase expression. Repetitive exposure to TG02 did not generate an acquired TG02 resistance phenotype, but accumulation of MCL-1, loss of c-MYC, or senescence. TG02 is a highly potent apoptosis-inducing agent in glioma cells in vitro. Caspase inhibition does not rescue TG02-treated cells and repetitive exposure fails to confer acquired resistance, supporting the clinical evaluation of TG02 in glioblastoma.

Epidermal growth factor receptor and ligand family expression and activity in glioblastoma.

Epidermal growth factor family of receptor tyrosine kinases (ERBB) family cell surface receptors, including epidermal growth factor receptor (EGFR/ERBB1), are phosphorylated upon binding by various EGF family ligands and signal via multiple kinase pathways. EGFR signaling is enhanced because of mutational activation of EGFR in almost half of glioblastomas, the most common malignant primary brain tumor. Therapeutic targeting of EGFR in glioblastoma has remained largely unsuccessful. Here, we profiled nine long-term (LTC) and five glioma-initiating (GIC) cell lines for expression and activation of ERBB family receptors and expression of their ligands. Receptors and ligands were abundantly expressed, with patterns overall similar to glioblastoma expression profiles in vivo as deposited in The Cancer Genome Atlas database. No differences between LTC and GIC emerged. Irrespective of ligand or receptor expression, neither an EGFR antibody, erbitux, nor an EGFR tyrosine kinase inhibitor, gefitinib, were particularly active against LTC or GIC at clinically relevant concentrations. Self-renewal capacity of GIC was severely compromised by epidermal growth factor (EGF) withdrawal, but rescued by transforming growth factor alpha (TGF-α), although not by neuregulin-1 (NRG-1). Subcellular fractionation indicated high levels of nuclear phosphorylated EGFR in all LTC and GIC. In LN-229 cells, pERBB2 and pERBB3 were also detected in the nucleus. Nuclear pERBB2 was less sensitive, whereas pERBB3 was induced, in response to gefitinib. This study provides an extensive characterization of human glioma cell models, including stem-like models, with regard to ERBB receptor/ligand expression and signaling. Redundant signaling involving multiple ERBB family ligands and receptors may contribute to the challenges of developing more effective EGFR-targeted therapies for glioblastoma.