Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor Responses .

B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody-drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation and GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA).

A Review of Specific Biomarkers of Chronic Renal Injury and Their Potential Application in Nonclinical Safety Assessment Studies.

A host of novel renal biomarkers have been developed over the past few decades which have enhanced monitoring of renal disease and drug-induced kidney injury in both preclinical studies and in humans. Since chronic kidney disease (CKD) and acute kidney injury (AKI) share similar underlying mechanisms and the tubulointerstitial compartment has a functional role in the progression of CKD, urinary biomarkers of AKI may provide predictive information in chronic renal disease. Numerous studies have explored whether the recent AKI biomarkers could improve upon the standard clinical biomarkers, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio, for predicting outcomes in CKD patients.

Congenital Unilateral Renal Aplasia in a Cynomolgus Monkey () With Investigation Into Potential Pathogenesis.

We describe and characterize unilateral renal aplasia in a cynomolgus monkey () from a chronic toxicology study adding to the limited histopathology reports of congenital renal anomalies in macaques. In the current case, the affected kidney was macroscopically small and characterized microscopically by a thin cortex with an underdeveloped medulla and an absent papilla. The remnant medulla lacked a corticomedullary junction and contained only a few irregular collecting duct-like structures.

Expression of Hematopoietic Stem and Endothelial Cell Markers in Canine Hemangiosarcoma.

Several chemicals and pharmaceuticals increase the incidence of hemangiosarcomas (HSAs) in mice, but the relevance to humans is uncertain. Recently, canine HSAs were identified as a powerful tool for investigating the pathogenesis of human HSAs. To characterize the cellular phenotype of canine HSAs, we evaluated immunoreactivity and/or messenger RNA (mRNA) expression of markers for hematopoietic stem cells (HSCs), endothelial cells (ECs), a tumor suppressor protein, and a myeloid marker in canine HSAs.

Author Correction: Targeting CLDN18.2 by CD3 Bispecific and ADC Modalities for the Treatments of Gastric and Pancreatic Cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Intrarenal Renin-Angiotensin System Involvement in the Pathogenesis of Chronic Progressive Nephropathy-Bridging the Informational Gap Between Disciplines.

Chronic progressive nephropathy (CPN) is the most commonly encountered spontaneous background finding in laboratory rodents. Various theories on its pathogenesis have been proposed, but there is a paucity of data regarding specific mechanisms or physiologic pathways involved in early CPN development. The current CPN mechanism of action for tumorigenesis is largely based on its associated increase in tubular cell proliferation without regard to preceding subcellular degenerative changes.

Targeting CLDN18.2 by CD3 Bispecific and ADC Modalities for the Treatments of Gastric and Pancreatic Cancer.

Human CLDN18.2 is highly expressed in a significant proportion of gastric and pancreatic adenocarcinomas, while normal tissue expression is limited to the epithelium of the stomach. The restricted expression makes it a potential drug target for the treatment of gastric and pancreatic adenocarcinoma, as evidenced by efforts to target CLDN18.

Kidney Pathology and Investigative Nephrotoxicology Strategies Across Species.

Drug-induced kidney toxicity is a significant contributor to acute kidney injury. Nephrotoxic drugs need to be identified during nonclinical testing to highlight potential risk translatable to the intended patient population. When nonclinical kidney toxicity signals arise, scientists and physicians affiliated with clinical trials need to be familiar with commonly encountered drug-induced perturbations in the kidney, terminology, and how these changes relate to clinical risk.

Drug-induced Glomerulonephritis: The Spectre of Biotherapeutic and Antisense Oligonucleotide Immune Activation in the Kidney.

Prevalence of immune-mediated glomerulonephritis has increased in preclinical toxicity studies, with more frequent use of biotherapeutic agents (especially antigenic humanized molecules) and antisense oligonucleotide (ASO) therapies. Immune complex disease affects a small number of study monkeys, often correlates with antidrug antibody (ADA) titers, and occurs at a dose that favors immune complex formation or impedes clearance. While preclinical glomerulonephritis often fails to correlate with evidence of glomerular or vascular injury in human clinical trials and is not considered predictive, additional animal investigative immunohistochemical work may be performed to substantiate evidence for immune complex pathogenesis.

From the Cover: Fenretinide, Troglitazone, and Elmiron Add to Weight of Evidence Support for Hemangiosarcoma Mode-of-Action From Studies in Mice.

Pharmaceuticals and chemicals produce hemangiosarcomas (HS) in mice, often by nongenotoxic, proliferative mechanisms. A mode-of-action (MOA) for hemangiosarcoma was proposed based on information presented at an international workshop (Cohen et al., Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance.

Induction of endogenous retroelements as a potential mechanism for mouse-specific drug-induced carcinogenicity.

A number of chemical compounds have been shown to induce liver tumors in mice but not in other species. While several mechanisms for this species-specific tumorigenicity have been proposed, no definitive mechanism has been established. We examined the effects of the nongenotoxic rodent hepatic carcinogen, WY-14,643, in male mice from a high liver tumor susceptible strain (C3H/HeJ), and from a low tumor susceptible strain (C57BL/6).

Liver Microvascular Injury and Thrombocytopenia of Antibody-Calicheamicin Conjugates in Cynomolgus Monkeys-Mechanism and Monitoring.

Adverse reactions reported in patients treated with antibody-calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury, and identify potential safety biomarkers. Cynomolgus monkeys were dosed intravenously at 6 mg/m/dose once every 3 weeks with a nonbinding antibody-calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab ozogamicin.

Hemodynamic correlates of drug-induced vascular injury in the rat using high-frequency ultrasound imaging.

Several classes of drugs have been shown to cause drug-induced vascular injury (DIVI) in preclinical toxicity studies. Measurement of blood flow and vessel diameter in numerous vessels and across various tissues by ultrasound imaging has the potential to be a noninvasive translatable biomarker of DIVI. Our objective was to demonstrate the utility of high-frequency ultrasound imaging for measuring changes in vascular function by evaluating blood flow and vessel diameter in the superior mesenteric arteries (SMA) of rats treated with compounds that are known to cause DIVI and are known vasodilators in rat: fenoldopam, CI-1044, and SK&F 95654.

Increased serum enzyme levels associated with kupffer cell reduction with no signs of hepatic or skeletal muscle injury.

Macrophage colony-stimulating factor (M-CSF) is a hematopoietic growth factor that is responsible for the survival and proliferation of monocytes and the differentiation of monocytes into macrophages, including Kupffer cells (KCs) in the liver. KCs play an important role in the clearance of several serum enzymes, including aspartate aminotransferase and creatine kinase, that are typically elevated as a result of liver or skeletal muscle injury. We used three distinct animal models to investigate the hypothesis that increases in the levels of serum enzymes can be the result of decreases in KCs in the apparent absence of hepatic or skeletal muscle injury.

Effects of the histamine H1 antagonist chlorcyclizine on rat fetal palate development.

Background: The effects of histamine H1 antagonist chlorcyclizine on rat palate development were characterized following in utero exposure.

Methods: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg chlorcyclizine on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg chlorcyclizine at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR.

Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium.

The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.

Towards consensus practices to qualify safety biomarkers for use in early drug development.

Application of any new biomarker to support safety-related decisions during regulated phases of drug development requires provision of a substantial data set that critically assesses analytical and biological performance of that biomarker. Such an approach enables stakeholders from industry and regulatory bodies to objectively evaluate whether superior standards of performance have been met and whether specific claims of fit-for-purpose use are supported. It is therefore important during the biomarker evaluation process that stakeholders seek agreement on which critical experiments are needed to test that a biomarker meets specific performance claims, how new biomarker and traditional comparators will be measured and how the resulting data will be merged, analyzed and interpreted.

Targeted disruption of murine organic anion-transporting polypeptide 1b2 (Oatp1b2/Slco1b2) significantly alters disposition of prototypical drug substrates pravastatin and rifampin.

Organic anion-transporting polypeptides (OATP) 1B1 and 1B3 are widely acknowledged as important and rate-limiting to the hepatic uptake of many drugs in clinical use. Accordingly, to better understand the in vivo relevance of OATP1B transporters, targeted disruption of murine Slco1b2 gene was carried out. It is noteworthy that Slco1b2(-/-) mice were fertile, developed normally, and exhibited no overt phenotypic abnormalities.

Expression of Ki-67 in the uterus during various stages of the estrous cycle in rats.

Rats have an average estrous cycle of 4-5 days. There are four phases (proestrus, estrus, metesterus, and diestrus) in the estrous cycle in rodents. Histologic staging of the rodent estrous cycle is challenging and requires expertise.

A practical method to determine the amount of tissue to analyze using laser scanning cytometry.

Background: Laser scanning cytometry (LSC) is a new technology similar to flow cytometry but generates data from analysis of successive microscopic fields. Unlike its use in other applications, LSC-generated data are not random when used for tissue sections, but are dependent on the microanatomy of the tissue and the distribution and expression of the protein under investigation. For valid LSC analysis, the data generated requires the evaluation of a sufficient tissue area to ensure an accurate representation of expression within the tissue of interest.

Detection of cytokine protein expression in mouse lung homogenates using suspension bead array.

Background: The objective for this present study was to determine whether or not suspension bead array is a feasible method to detect changes in cytokine protein expression in mouse lung tissue homogenates. Here, we report on suspension bead array as a feasible method for detection of lipopolysaccharide (LPS)-evoked changes in cytokine protein expression in mouse lung tissue homogenates.

Materials And Methods: Mice were treated (0.

Identification of potential genomic biomarkers of hepatotoxicity caused by reactive metabolites of N-methylformamide: Application of stable isotope labeled compounds in toxicogenomic studies.

The inability to predict if a metabolically bioactivated compound will cause toxicity in later stages of drug development or post-marketing is of serious concern. One approach for improving the predictive success of compound toxicity has been to compare the gene expression profile in preclinical models dosed with novel compounds to a gene expression database generated from compounds with known toxicity. While this guilt-by-association approach can be useful, it is often difficult to elucidate gene expression changes that may be related to the generation of reactive metabolites.