A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia.

Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naive patients.

Population Pharmacokinetics of Brentuximab Vedotin in Patients With CD30-Expressing Hematologic Malignancies.

Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for treating certain patients with CD30-expressing hematologic malignancies. Its primary mechanism of action is the targeted delivery of a microtubule-disrupting agent, monomethyl auristatin E (MMAE), to CD30-expressing cells. A population pharmacokinetic (PopPK) analysis was conducted to characterize the PK of ADC and unconjugated MMAE in patients with CD30-expressing hematologic malignancies by compartmental analysis and to evaluate the effects of covariates on PK of the ADC.

Brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive haematologic malignancies and hepatic or renal impairment.

Aims: Brentuximab vedotin, an antibody-drug conjugate (ADC), selectively delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) into CD30-expressing cells. The pharmacokinetics of brentuximab vedotin have been characterized in patients with CD30-positive haematologic malignancies. The primary objective of this phase 1 open label evaluation was to assess the pharmacokinetics of brentuximab vedotin in patients with hepatic or renal impairment.

Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma.

Purpose: This first-in-human study evaluated the CD70-targeted antibody-drug conjugate SGN-75 in patients with relapsed or refractory CD70-positive non-Hodgkin lymphoma (NHL) or metastatic renal cell carcinoma (RCC). Methods SGN-75 was administered intravenously to 58 patients (39 RCC, 19 NHL) every 3 weeks (Q3Wk; doses escalated from 0.3 to 4.

Absorption, distribution, metabolism, and excretion considerations for the development of antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a class of therapeutics that are designed to deliver potent small-molecule drugs selectively to cells that express a specific target antigen while limiting systemic exposure to the drug. This is accomplished by conjugating a potent drug onto an antibody-based therapeutic with a linker that is exquisitely stable in plasma. The development of an effective ADC requires optimizing a number of design elements and an extensive understanding of absorption, distribution, metabolism/catabolism, and elimination (ADME) processes for the ADC construct.

Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors.

Purpose: To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of the 24-h continuous intravenous (CIV) infusion of MK-0457, a novel pan-Aurora kinase inhibitor, in patients with advanced solid tumors and to determine the bioavailability of an oral dose of 100 mg MK-0457.

Study Design: MK-0457 was administered as a 24-h CIV infusion every 21 days. Dose escalation proceeded per toxicity criteria.

Cytoprotection of human endothelial cells from menadione cytotoxicity by caffeic acid phenethyl ester: the role of heme oxygenase-1.

Caffeic acid phenethyl ester (CAPE), derived from various plant sources, has been shown to ameliorate ischemia/reperfusion injury in vivo, and this has been attributed to its ability to reduce oxidative stress. Here we investigated the cytoprotection of CAPE against menadione-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) to evaluate potential gene expression involvement. CAPE exhibited dose-dependent cytoprotection of HUVEC.

Application of scaling factors in simultaneous modeling of microarray data from diverse chips.

Purpose: Microarrays have been utilized in many biological, physiological and pharmacological studies as a high-throughput genomic technique. Several generations of Affymetrix GeneChip microarrays are widely used in gene expression studies. However, differences in intensities of signals for different probe sets that represent the same gene on various types of Affymetrix chips make comparison of datasets complicated.

Geldanamycin prevents hemorrhage-induced ATP loss by overexpressing inducible HSP70 and activating pyruvate dehydrogenase.

Hemorrhage in mice results in decreased ATP levels in the jejunum, lung, kidney, heart, and brain but not in liver tissue lysates, albeit at variable levels and time kinetics. The decreased protein expression and activity of pyruvate dehydrogenase (PDH) accounted for the hemorrhage-induced ATP loss. Treatment with geldanamycin (GA; 1 microg/g body wt), a known inducer of heat shock protein (HSP)70, inhibited the hemorrhage-induced ATP loss in the jejunum, lung, heart, kidney, and brain.

Geldanamycin treatment inhibits hemorrhage-induced increases in KLF6 and iNOS expression in unresuscitated mouse organs: role of inducible HSP70.

The aim of this study was to determine whether hemorrhage affects the levels of a variety of stress-related proteins and whether changes can be inhibited by drugs reported to provide protection from ischemia and reperfusion injury. Male Swiss Webster mice were subjected to a 40% hemorrhage without resuscitation. Western blot analysis indicated that c-Jun (an AP-1 protein), Kruppel-like factor 6 (KFL6), and inducible nitric oxide synthase (iNOS) were upregulated sequentially in that order.

Effect of interleukin-1beta and tumor necrosis factor-alpha on gene expression in human endothelial cells.

Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are two major cytokines that rise to relatively high levels during systemic inflammation, and the endothelial cell (EC) response to these cytokines may explain some of the dysfunction that occurs. To better understand the cytokine-induced responses of EC at the gene expression level, human umbilical vein EC were exposed to IL-1beta or TNF-alpha for various times and subjected to cDNA microarray analyses to study alterations in their mRNA expression. Of approximately 4,000 genes on the microarray, expression levels of 33 and 58 genes appeared to be affected by treatment with IL-1beta and TNF-alpha, respectively; 25 of these genes responded to both treatments.