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1.
Toxicol Appl Pharmacol ; 435: 115811, 2022 01 15.
Article in English | MEDLINE | ID: mdl-34896194

ABSTRACT

Invasive Staphylococcus aureus (S. aureus) infections are a leading cause of death and not effectively treated with prolonged standard of care antibiotics. A novel THIOMAB™ antibody antibiotic conjugate (TAC) was developed that uses a bacterial-wall specific antibody to deliver the antibiotic (dmDNA31, a rifamycin analogue) to bacteria to minimize toxicities typically seen with prolonged use of traditional antibiotics. The TAC nonclinical toxicology package included repeat dose rat and cynomolgus monkey toxicology studies for 8 weekly intravenous (IV) doses, a 7-day daily repeat dose IV toxicology study of dmDNA31 and an assessment of genotoxicity, cardiovascular toxicity, neurotoxicity and sperm parameters. TAC and dmDNA31 were well tolerated in rats and monkeys, and there was no evidence of genotoxicity, cardiovascular toxicity or neurotoxicity. Non-adverse findings were observed and included blue discoloration in skin, blood, etc. due to the blue color of dmDNA31, increased globulin due to the high doses of antibodies, and abnormal sperm morphology of small heads in male rats with no histopathology correlate in testis. This is an example of antibody-mediated delivery of an antibiotic that has the potential to offer a more effective way of eradicating infection while providing a better safety profile compared to traditional antibiotics.


Subject(s)
Immunotoxins/toxicity , Immunotoxins/therapeutic use , Staphylococcal Infections/drug therapy , Administration, Intravenous , Animals , Cardiovascular Diseases/chemically induced , Cell Wall/chemistry , Drug Delivery Systems , Female , Globulins/metabolism , Macaca fascicularis , Male , Mutagenicity Tests , Nervous System Diseases/chemically induced , Rats , Rats, Sprague-Dawley , Spermatozoa/drug effects , Staphylococcal Infections/microbiology , Testis/pathology
2.
Toxicol Appl Pharmacol ; 418: 115494, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33722668

ABSTRACT

Tumor progression locus 2 (Tpl2, gene name MAP3K8), a mitogen-activated protein kinase, is widely expressed in immune and non-immune cells to integrate tumor necrosis factor (TNF), toll-like receptors (TLRs), and interleukin-1 (IL1) receptor signaling to regulate inflammatory response. Given its central role in inflammatory response, Tpl2 is an attractive small molecule drug target. However, the role of Tpl2 as an oncogene or tumor suppressor gene remains controversial, and its function outside immune cells is not understood. We therefore utilized a Tpl2 kinase dead (Tpl2-KD) mouse model in an 18-month aging study to further elucidate Tpl2 effects on lifespan and chronic disease. Histopathological studies revealed the incidence and severity of spontaneous tumors and non-neoplastic lesions were comparable between wild type and Tpl2-KD mice. The only finding was that male Tpl2-KD mice had higher bodyweight and an increased incidence of liver steatosis, suggesting a sex-specific role for Tpl2 in hepatic lipid metabolism. In conclusion, loss of Tpl2 kinase activity did not lead to increased tumorigenesis over aging in mice but affected likely alterations in lipid metabolism in male animals.


Subject(s)
Fatty Liver/enzymology , Inflammation/enzymology , Liver/enzymology , MAP Kinase Kinase Kinases/metabolism , Neoplasms/metabolism , Proto-Oncogene Proteins/metabolism , Age Factors , Animals , Fatty Liver/genetics , Fatty Liver/pathology , Female , Genotype , Inflammation/genetics , Lipid Metabolism , Liver/pathology , MAP Kinase Kinase Kinases/deficiency , MAP Kinase Kinase Kinases/genetics , Male , Mice, Inbred C57BL , Mice, Knockout , Neoplasms/genetics , Neoplasms/pathology , Phenotype , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/genetics , Sex Factors
3.
Drug Metab Dispos ; 48(11): 1161-1168, 2020 11.
Article in English | MEDLINE | ID: mdl-32839277

ABSTRACT

Invasive Staphylococcus aureus infection is a leading cause of infectious disease-related deaths because S. aureus survives within host phagocytic cells, from which the bacteria are not adequately eliminated using current antibiotic treatments. Anti-S. aureus THIOMAB antibody-antibiotic conjugate (TAC), an anti-S. aureus antibody conjugated with antibiotic payload dmDNA31, was designed to deliver antibiotics into phagocytes, thereby killing intracellular S. aureus Herein, we present the distribution, metabolism/catabolism, and elimination properties for this modality. The tissue distribution of TAC and the release and elimination of its payload dmDNA31 were characterized in rats using multiple approaches. Intravenous injection of unconjugated [14C]dmDNA31 to rats resulted in a rapid clearance in both systemic circulation and tissues, with biliary secretion as the major route of elimination. Six major metabolites were identified. When [14C]dmDNA31 was conjugated to an antibody as TAC and administered to rat intravenously, a sustained exposure was observed in both systemic circulation and tissues. The dmDNA31 in blood and tissues mainly remained in conjugated form after administering TAC, although minimal deconjugation of dmDNA31 from TAC was also observed. Several TAC catabolites were identified, which were mainly eliminated through the biliary-fecal route, with dmDNA31 and deacetylated dmDNA31 as the most abundant catabolites. In summary, these studies provide a comprehensive characterization of the distribution, metabolism/catabolism, and elimination properties of TAC. These data fully support further clinical development of TAC for the invasive and difficult-to-treat S. aureus infection. SIGNIFICANCE STATEMENT: The present studies provide a comprehensive investigation of the absorption, distribution, metabolism/catabolism, and elimination of the first antibody-antibiotic conjugate developed for the treatment of an infectious disease. Although many antibody-drug conjugates are in development for various disease indications, only a limited amount of absorption, distribution, metabolism/catabolism, and elimination information is available in the literature. This study demonstrates the use of radiolabeling technology to delineate the absorption, distribution, metabolism/catabolism, and elimination properties of a complex modality and help address the key questions related to clinical pharmacological studies.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Antibodies, Bacterial/pharmacology , Immunoconjugates/pharmacokinetics , Animals , Anti-Bacterial Agents/administration & dosage , Female , Humans , Immunoconjugates/administration & dosage , Injections, Intravenous , Male , Models, Animal , Rats , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/immunology , Tissue Distribution
4.
J Leukoc Biol ; 107(6): 941-952, 2020 06.
Article in English | MEDLINE | ID: mdl-31985117

ABSTRACT

Receptor interacting protein kinase 1 (RIP1) is a critical effector of inflammatory responses and cell death activation. Cell death pathways regulated by RIP1 include caspase-dependent apoptosis and caspase-independent necroptosis. The kinase activity of RIP1 has been associated with a number of inflammatory, neurodegenerative, and oncogenic diseases. In this study, we use the RIP1 kinase inhibitor GNE684 to demonstrate that RIP1 inhibition can effectively block skin inflammation and immune cell infiltrates in livers of Sharpin mutant (Cpdm; chronic proliferative dermatitis) mice in an interventional setting, after disease onset. On the other hand, genetic inactivation of RIP1 (RIP1 KD) or ablation of RIP3 (RIP3 KO) or MLKL (MLKL KO) did not affect testicular pathology of aging male mice. Likewise, infection with vaccinia virus or with mouse gammaherpesvirus MHV68 resulted in similar viral clearance in wild-type, RIP1 KD, and RIP3 KO mice. In summary, this study highlights the benefits of inhibiting RIP1 in skin inflammation, as opposed to its lack of relevance for testicular longevity and the response to certain viral infections.


Subject(s)
Dermatitis/genetics , Herpesviridae Infections/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Skin/immunology , Vaccinia/genetics , Animals , Chronic Disease , Dermatitis/immunology , Dermatitis/pathology , Dermatitis/virology , Disease Models, Animal , Gammaherpesvirinae/immunology , Gammaherpesvirinae/pathogenicity , Gene Expression Regulation , Herpesviridae Infections/pathology , Herpesviridae Infections/virology , Inflammation , Liver/immunology , Liver/pathology , Liver/virology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Protein Kinase Inhibitors/pharmacology , Protein Kinases/deficiency , Protein Kinases/genetics , Protein Kinases/immunology , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptor-Interacting Protein Serine-Threonine Kinases/deficiency , Receptor-Interacting Protein Serine-Threonine Kinases/immunology , Signal Transduction , Skin/pathology , Skin/virology , Testis/immunology , Testis/pathology , Testis/virology , Vaccinia/immunology , Vaccinia/pathology , Vaccinia/virology , Vaccinia virus/immunology , Vaccinia virus/pathogenicity , Virus Replication/immunology
5.
MAbs ; 8(8): 1612-1619, 2016.
Article in English | MEDLINE | ID: mdl-27653831

ABSTRACT

DSTA4637A, a novel THIOMAB™ antibody antibiotic conjugate (TAC) against Staphylococcus aureus (S. aureus), is currently being investigated as a potential therapy against S. aureus infections. Structurally, TAC is composed of an anti-S. aureus antibody linked to a potent antibiotic, dmDNA31. The goal of the current study was to characterize the pharmacokinetics (PK) of TAC in mice, assess the effect of S. aureus infection on its PK, and evaluate its pharmacodynamics (PD) by measuring the bacterial load in various organs at different timepoints following TAC treatment. Plasma concentrations of 3 analytes, total antibody (TAb), antibody-conjugated dmDNA31 (ac-dmDNA31), and unconjugated dmDNA31, were measured in these studies. In non-infected mice (target antigen absent), following intravenous (IV) administration of a single dose of TAC, systemic concentration-time profiles of both TAb and ac-dmDNA31 were bi-exponential and characterized by a short distribution phase and a long elimination phase as expected for a monoclonal antibody-based therapeutic. Systemic exposures of both TAb and ac-dmDNA31 were dose proportional over the dose range tested (5 to 50 mg/kg). In a mouse model of systemic S. aureus infection (target antigen present), a single IV dose of TAC demonstrated PK behavior similar to that in the non-infected mice, and substantially reduced bacterial load in the heart, kidney, and bones on 7 and 14 d post dosing. These findings have increased our understanding of the PK and PK/PD of this novel molecule, and have shown that at efficacious dose levels the presence of S. aureus infection had minimal effect on TAC PK.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Antibodies, Bacterial/pharmacology , Antibodies, Monoclonal/pharmacokinetics , Immunoconjugates/pharmacokinetics , Staphylococcal Infections/drug therapy , Animals , Mice , Staphylococcus aureus
6.
Br J Pharmacol ; 168(2): 445-57, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22889168

ABSTRACT

BACKGROUND AND PURPOSE: The success of antibody-drug conjugates (ADCs) depends on the therapeutic window rendered by the differential expression between normal and pathological tissues. The ability to identify and visualize target expression in normal tissues could reveal causes for target-mediated clearance observed in pharmacokinetic characterization. TENB2 is a prostate cancer target associated with the progression of poorly differentiated and androgen-independent tumour types, and ADCs specific for TENB2 are candidate therapeutics. The objective of this study was to locate antigen expression of TENB2 in normal tissues, thereby elucidating the underlying causes of target-mediated clearance. EXPERIMENTAL APPROACH: A series of pharmacokinetics, tissue distribution and mass balance studies were conducted in mice using a radiolabelled anti-TENB2 ADC. These data were complemented by non-invasive single photon emission computed tomography - X-ray computed tomography imaging and immunohistochemistry. KEY RESULTS: The intestines were identified as a saturable and specific antigen sink that contributes, at least in part, to the rapid target-mediated clearance of the anti-TENB2 antibody and its drug conjugate in rodents. As a proof of concept, we also demonstrated the selective disposition of the ADC in a tumoural environment in vivo using the LuCaP 77 transplant mouse model. High tumour uptake was observed despite the presence of the antigen sink, and antigen specificity was confirmed by antigen blockade. CONCLUSIONS AND IMPLICATIONS: Our findings provide the anatomical location and biological interpretation of target-mediated clearance of anti-TENB2 antibodies and corresponding drug conjugates. Further investigations may be beneficial in addressing the relative contributions to ADC disposition from antigen expression in both normal and pathological tissues.


Subject(s)
Antigens/immunology , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Immunoconjugates/pharmacokinetics , Membrane Proteins/immunology , Neoplasm Proteins/immunology , Oligopeptides/pharmacokinetics , Animals , Cell Line, Tumor , Cytotoxins/chemistry , Heterocyclic Compounds, 1-Ring/chemistry , Immunoconjugates/chemistry , Male , Mice , Mice, SCID , Neoplasms/metabolism , Oligopeptides/chemistry , Pharmaceutical Preparations , Tissue Distribution
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