Toxicity Profiling

A lot of compounds, although efficacious, may fail to meet the acceptable toxicity profile. Toxicity profiling and testing is therefore an important facet of drug development. The objective is to ensure that the test substance is safe for further preclinical/clinical development.

Drugs research and development cost over $145 billion every year in the US only. One of the key contributors to these rising costs is unacceptable drug safety profile either detected during Phase 1 Clinical Trial (50-60%) or during Phase IV Post marketing surveillance where some severe side effects were unnoticed during the phase I clinical trial. This is what makes toxicity profiling so important. Of note, it has been described that in 30% of the studied cases the animals showed a toxic effect on a different organ compared to human (https://www.gwern.net/docs/dnb/2000-olson.pdf)

A549 cells were treated with test compounds in a 8 dose response curve. Both cell viability and cytotoxicity was assessed using CellTitre-Glo and LDH respectively. Staurosporine (a positive reference control compound) showed a significant reduction in cell viability when compared to untreated or vehicle control (***p<0.001; ±SEM).

HeLa cells were treated with Staurosporine for 4 hours at different concentrations ranging from 10µM to 125nM. Caspase-Glo 3/7® Reagent was added directly to cells in 96-well plates and incubated at room temperature for 30 minutes before recording luminescence (RLU). Each point represents the average of 3 replicates (error bars represent ±SEM).

Cytotoxic profile of a test antibody (1°Ab) in the presence of 2° antibody conjugated with-MMAE toxin. Viability of Kasumi-3 was analysed using Cell-Titer Glo Luminescence assay. A statistically significant decrease in Kasumi-3 cell viability was observed with concentrations above 0.01 nM. Data analysed by one-way ANOVA, followed by Dunnett’s post-hoc multiple comparison test (*p<0.02; **p<0.005; ***p<0.0003, <0.0001; ±SEM).

Acute kidney diseaseChronic kidney diseaseNephrotoxicity
Neutrophil gelatinase-associate lipocalin (NGAL)Asymmetric dimethylarginine (ADMA)N-acetyl-β-D-glucosaminidase (NAG)
interleukin-18 (IL18)Neutrophil gelatinase-associate lipocalin (NGAL)Glutathione S-transferases (GST)
Kidney Injury Molecule-1 (KIM1)Kidney Injury Molecule-1 (KIM-1)Gamma-glutamyltransferase (GGT)
Cystatic C (CST3)Liver-type Fatty acid binding protein (L-FABP)Kidney Injury Molecule-1 (KIM1)
Liver-type Fatty acid binding protein (L-FABP)Lactic dehydrogenase (LDH) 
Insulin like growth factor binding protein (IGFBP7)  
Tissue metallopeptidase inhibitor 2 (TIMP-2)  
 
HumanMouseRat
AlbuminClusterinAlbumin
ClusterinCystatin CCalbindin
Collagen IVEpithelial growth factorClusterin
Cystatin CInterferon gamma-induced protein 10Cystatin C
Glutathione S-transferasesKidney Injury Molecule-1Glutathione S-transferases
Interferon gamma-induced protein 10Lipocalin-2Interferon gamma-induced protein 10
Kidney Injury Molecule-1OsteopontinKidney Injury Molecule-1
Lipocalin-2ReninLipocalin-2
Liver-type Fatty acid binding proteinβ-2-MicroglobulinOsteopontin
Macrophage activator proteinTissue metallopeptidase inhibitor 2Tissue metallopeptidase inhibitor 2
Matrix Metalloproteinases (MMP9)Vascular Endothelial Growth FactorVascular Endothelial Growth Factor
Osteoactivin β-2-Microglobulin (β2M)
OsteopontinInterleukin 2,6,8,10 (IL2, IL 6, IL8, IL10)Interleukin 2,6,8,10 (IL2, IL 6, IL8, IL10)
Renin Trefoil factor 3
Trefoil factor 3  
a-1-Microglobulin  
Heat Shock Protein 70 (HSP70)  
Interleukin 2,6,8,10 (IL2, IL 6, IL8, IL10)  
 
HumanRats
Liver-Type Arginase 1 (ARG1)Liver-Type Arginase 1 (ARG1)
Malate dehydrogenase 1 (MDH1)aspartate transaminase 1 (GOT1)
α-glutathione S-transferase (GSTα)α-glutathione S-transferase (GSTα)
Sorbitol Dehydrogenase (SDH)Sorbitol Dehydrogenase (SDH)
5′-Nucleotidase/CD73 (5’-NT)5′-Nucleotidase (5′-NT/CD73).

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