A5030334559- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- CAR-T cell therapy research
- Cancer Research and Treatments
- Cell Adhesion Molecules Research
- Animal testing and alternatives
- Cancer Immunotherapy and Biomarkers
- Immunotoxicology and immune responses
- Epigenetics and DNA Methylation
- Biosimilars and Bioanalytical Methods
- Multiple Myeloma Research and Treatments
- Cancer Cells and Metastasis
- Radiopharmaceutical Chemistry and Applications
- Carcinogens and Genotoxicity Assessment
- Immune Cell Function and Interaction
- Immune cells in cancer
- Cancer Treatment and Pharmacology
- Gastric Cancer Management and Outcomes
- Lung Cancer Treatments and Mutations
- Heparin-Induced Thrombocytopenia and Thrombosis
- Platelet Disorders and Treatments
- Immunotherapy and Immune Responses
- DNA Repair Mechanisms
- Cytokine Signaling Pathways and Interactions
- Statistical Methods in Clinical Trials
AbbVie (United States)
2020-2025
Pfizer (United States)
2012-2022
Pearl River Community College
2021
Pfizer (United Kingdom)
2011
Sanofi (France)
2011
École Nationale Vétérinaire d'Alfort
2009
Université Sorbonne Paris Nord
2001-2004
New York State College of Veterinary Medicine
1998
Cornell University
1996-1998
Abstract Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches needed overcome resistance 1,2 . The protein tyrosine phosphatases PTPN2 PTPN1 central regulators of inflammation, their genetic deletion in either tumour cells or immune promotes anti-tumour immunity 3–6 However, challenging drug targets; particular, the active site has been considered undruggable. Here we present discovery characterization...
PTK7 is a tumor-initiating cell antigen, which can be targeted with an antibody-drug conjugate to confer sustained tumor regressions.
This study reports the evaluation of four urinary biomarkers renal toxicity, α-glutathione-S-transferase (α-GST), μ-GST, clusterin, and papillary antigen-1 (RPA-1), in male Sprague-Dawley Han-Wistar rats given cisplatin, gentamicin, or N-phenylanthranilic acid (NPAA). Kidney injury was diagnosed histopathologically, according to site/nature injury, graded for severity. The area under receiver operating characteristic (ROC) curve used compare diagnostic accuracy each exploratory biomarker...
Abstract Background The clinical success of immune checkpoint inhibitors demonstrates that reactivation the human system delivers durable responses for some patients and represents an exciting approach cancer treatment. An important class preclinical in vivo models immuno-oncology is immunocompetent mice bearing mouse syngeneic tumors. To facilitate translation studies into human, we characterized genomic, transcriptomic, protein expression a panel ten commonly used tumor cell lines grown...
Immune checkpoint inhibitors (ICI) targeting PD1, PDL1, or CTLA4 are associated with immune-related adverse events (irAE) in multiple organ systems including myocarditis. The pathogenesis and early diagnostic markers for ICI-induced myocarditis poorly understood, there is currently a lack of laboratory animal model to enhance our understanding. We aimed develop such using cynomolgus monkeys.Chinese-origin monkeys were dosed intravenously vehicle nivolumab 20 mg/kg plus ipilimumab 15 once...
Purpose: Adverse reactions reported in patients treated with antibody-calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab include thrombocytopenia sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize liver injury, identify potential safety biomarkers.Experimental Design: Cynomolgus monkeys were dosed intravenously at 6 mg/m2/dose once every 3 weeks a nonbinding conjugate...
Abstract The approval of ado-trastuzumab emtansine (T-DM1) in HER2+ metastatic breast cancer validated HER2 as a target for HER2-specific antibody–drug conjugates (ADC). Despite its demonstrated clinical efficacy, certain inherent properties within T-DM1 hamper this compound from achieving the full potential targeting HER2-expressing solid tumors with ADCs. Here, we detail discovery PF-06804103, an anti-HER2 ADC designed to have widened therapeutic window compared T-DM1. We utilized...
Gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. Here, we demonstrate potent, tumor-selective efficacy with PF-07062119, a T-cell engaging CD3 bispecific targeting tumors expressing Guanylyl Cyclase C (GUCY2C), which is expressed widely across colorectal cancer other gastrointestinal malignancies. In addition, to address immune evasion mechanisms, explore combinations checkpoint blockade agents antiangiogenesis therapy.PF-07062119...
Nonhuman primates (NHPs) have been and remain a highly valuable animal model with an essential role in translational research pharmaceutical drug development. Based on current regulatory guidelines, the nonclinical safety of novel therapeutics should be evaluated relevant species, which commonly includes NHPs for biotherapeutics. Given practical ethical limitations availability and/or use line widely accepted guiding “3Rs” (replace, reduce, refine) principles, many approaches considered to...
The pace of technological innovation in the pharmaceutical industry, like many other sectors, is accelerating rapidly. This not only reshaping how Research and Development (R&D) conducted (e.g., introduction novel models, endpoints, instrumentation) but also influencing types therapeutic modalities being developed. In addition, societal regulatory expectations have evolved to emphasize approaches that align with 4Rs principles (Replacement, Reduction, Refinement, Responsibility)...
Kidney is a major target organ in preclinical studies. In recent years, intense research has been undertaken to characterize novel renal toxicity biomarkers. this context, we studied nephron segment specific antibodies against aquaporin-1 (AQP-1), α-glutathione-S-transferase (alpha-GST), Tamm-Horsfall protein (TH), calbindin-D 28K (CalD), and aquaporin-2 (AQP-2), using an immunoperoxidase method on formalin-fixed paraffin-embedded kidney tissues of dogs, rats, mice, Cynomolgus monkeys. AQP-1...
Differences were examined between male and female Sprague-Dawley rats in basal levels of a wide range urinary biomarkers, including 7 recently qualified biomarkers. The data generated from urine samples collected on 3 occasions untreated included study the effect gentamicin nephrotoxicity renal reported companion article this journal (Gautier et al. 2014). performance multiple assays (9 singleplex 2 multiplex platforms Rules Based Medicine [RBM] Meso Scale Discovery [MSD]) was evaluated,...
Differences were examined between male and female Sprague-Dawley rats in the response of 16 urinary biomarkers (measured using several assay platforms) to renal injury produced by gentamicin administered subcutaneously for 10 days at a dosage 75 mg/kg. Urinary expressed as fold difference from contemporaneous controls histopathology assessed after 3 doses. On day 4, minimal proximal tubular changes observed microscopically all males but no females; on 11, more extensive severe was similar...
Abstract Extra domain B splice variant of fibronectin (EDB+FN) is an extracellular matrix protein (ECM) deposited by tumor-associated fibroblasts, and associated with tumor growth, angiogenesis, invasion. We hypothesized that EDB+FN a safe abundant target for therapeutic intervention antibody–drug conjugate (ADC). describe the generation, pharmacology, mechanism action, safety profile ADC specific (EDB-ADC). broadly expressed in stroma pancreatic, non–small cell lung (NSCLC), breast,...
Abstract Administration of a novel and selective small molecule integrin αvβ6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction epithelial proliferative changes urinary bladder 2 animals, absence test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae cells, variable cytologic atypia, high mitotic rate, without invasion into tunica muscularis. Morphologic features patterns tumor growth...
Contents The objective of this study was to confirm in various breeds dogs the efficacy and safety a parturition induction treatment described be successful Beagle dogs. Parturition induced seven sized pregnant bitches different breeds, with 15 mg aglepristone per kg at day 59–61 post‐estimated ovulation day, followed 24 h later by 0.15 IU oxytocin subcutaneous injections every 2 h. Two were small‐sized (<10 kg), three large‐sized (30–40 kg) two giant (>40 kg). results compared control...
5,9-Dimethyldibenzo[c,g]carbazole (DMDBC) is a synthetic derivative of the environmental pollutant 7H-dibenzo-[c,g]carbazole. DMDBC potent genotoxic carcinogen specific for mouse liver. Using Muta™Mouse lacZ transgenic model and positive selection assay, we measured mutant frequency (MF) in liver 28 days after single s.c. administration at 3, 10, 30, 90 or 180 mg/kg. MF remained low 3 10 mg/kg, but increased markedly from 30 mg/kg onwards. To investigate reason this non-linear response,...
Aberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody conjugates (NOTCH3-ADCs) by bioconjugation of an auristatin microtubule inhibitor through a protease cleavable linker to two antibodies differential abilities inhibit signaling. The inhibitory rapidly induces ligand-independent receptor clustering internalization both caveolin clathrin-mediated...
The purpose of this work was to investigate the impact cell proliferation on liver mutagenesis. genotoxic hepatocarcinogen 5,9-dimethyldibenzo[c,g]carbazole (DMDBC) administered lacZ transgenic Muta™Mice at a non-hepatotoxic dose 10 mg/kg, which induces only slight increase in mutant frequency (MF). To determine if stimuli enhanced DMDBC mutagenicity, MF analyzed mice first receiving then ~2 weeks later, either carbon tetrachloride (CCl4, cytotoxic agent inducing regenerative proliferation)...
We describe 4 young male Doberman Pinschers (3 littermates and 1 unrelated dog) with a syndrome resembling idiopathic or noncirrhotic portal hypertension of humans. Each dog was evaluated for hepatopathy resulting in hypertension, development portosystemic collateral vessels, hepatic encephalopathy. These dogs differ from previous reports insufficiency associated acquired systemic shunting by their lack intrahepatic arteriovenous fistulae, vein atresia, fibrosis. Clinicopathologic features...
Abstract Activation and mutation of the NOTCH signaling pathway is oncogenic in many tissue types target multiple anti-cancer therapies currently clinical development. Initial therapeutic strategies designed to have focused on inhibition aberrant signaling, but can undesirable side-effects or insufficient anti-tumor activity. Antibody drug conjugates (ADCs) are an emerging modality that equips antibodies with potent cytotoxic payloads be directly delivered tumor cells. We developed compared...