A5049564431- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Cell Adhesion Molecules Research
- Radiopharmaceutical Chemistry and Applications
- Lung Cancer Treatments and Mutations
- IL-33, ST2, and ILC Pathways
- Cancer Cells and Metastasis
- Computational Drug Discovery Methods
- Cancer Genomics and Diagnostics
- Gastric Cancer Management and Outcomes
- Glycosylation and Glycoproteins Research
- Asthma and respiratory diseases
- Cancer Treatment and Pharmacology
- Pediatric health and respiratory diseases
- Advanced Breast Cancer Therapies
- Synthesis and Reactions of Organic Compounds
- Estrogen and related hormone effects
- Immunotherapy and Immune Responses
- RNA Interference and Gene Delivery
- Angiogenesis and VEGF in Cancer
- Peptidase Inhibition and Analysis
- Immune Cell Function and Interaction
- Food Allergy and Anaphylaxis Research
- Toxin Mechanisms and Immunotoxins
- Click Chemistry and Applications
Pfizer (United States)
2013-2024
The University of Texas MD Anderson Cancer Center
2011
Pfizer (United Kingdom)
2011
Women's Health Research Institute
2007
Mount Sinai Medical Center
2006
University of Michigan
1995
Howard Hughes Medical Institute
1995
Ischemia/reperfusion (I/R) injury associated with renal transplantation may influence both early graft function and late changes. The initial (</= 7 d) events of warm in situ perfused cold ischemia native kidneys uninephrectomized rats were examined. mRNA expression the adhesion molecule, E-selectin, peaked within 6 h; PMNs infiltrated parallel. T cells macrophages entered injured kidney by 2-5 d; upregulation MHC class II antigen suggested increased immunogenicity organ. Th1 products (IL-2,...
Abstract Antibody–drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop novel ADC that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells (TIC), which comprise most aggressive cell population in tumor. optimized anti-5T4 (A1mcMMAF) by sulfydryl-based conjugation humanized A1 antibody tubulin inhibitor monomethylauristatin F (MMAF) via maleimidocaproyl linker. A1mcMMAF exhibited potent vivo antitumor...
As part of our efforts to develop new classes tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism critical acetate ester. A two-pronged strategy was employed address this metabolism. First, the hydrolytically labile ester replaced by carbamate functional group resulting more stable retained potency cellular assays. Second, site-specific conjugation order design...
Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and time to recurrence following treatment. Here, we integrate multiple experimental models clinicopathologic analysis of delineate a cellular hierarchy NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells worse clinical outcome Coexpression factors involved epithelial-to-mesenchymal transition were observed undifferentiated but not tumor...
Human studies using Abs to two different, nonoverlapping epitopes of IL-13 suggested that epitope specificity can have a clinically significant impact on clearance IL-13. We propose Ab modulation interaction with IL-13Rα2 underlies this effect. Two were administered healthy subjects and mild asthmatics in separate dose-ranging allergen-challenge studies. IMA-638 allows IL-13Rα1 or but blocks recruitment IL-4Rα the IL-13/IL-13Rα1 complex, whereas IMA-026 competes IL-13Rα2. found ∼10-fold...
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...
Summary Interleukin‐4 ( IL ‐4) and ‐13 are critical drivers of immune activation inflammation in ulcerative colitis, asthma other diseases. Because these cytokines may have redundant function, dual targeting holds promise for achieving greater efficacy. We recently described a bifunctional therapeutic ‐4 developed on novel protein scaffold, generated by combining specific binding domains an optimal configuration using appropriate linker regions. In the current study, ‐4/ antagonist was...
Factor VIII is the coagulation factor deficient in X-chromosome-linked bleeding disorder hemophilia A. homologous to blood V, both having a domain structure of A1-A2-B-A3-C1-C2. Previous transfection studies demonstrated that 10-fold less efficiently expressed than factor, V. The inefficient expression correlated with interaction primary translation product protein chaperonin BiP lumen endoplasmic reticulum. In contrast, V was not detected association and secreted efficiently. To determine...
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Antibody-drug conjugates (ADC) represent a promising therapeutic modality for managing cancer. Here, we report novel humanized ADC that targets the tetraspanin-like protein TM4SF1. TM4SF1 is highly expressed on plasma membranes of many human cancer cells and also endothelial lining tumor blood vessels. internalized upon interaction with antibodies. We hypothesized an against would inhibit growth directly by killing indirectly attacking vasculature. generated anti-human monoclonal antibody,...
Abstract P-selectin glycoprotein ligand-1 (PSGL-1) mediates the initial tethering of leukocytes to activated platelets and endothelium. We report molecular cloning characterization rat PSGL-1 gene. A neutralizing Ab was generated, its binding epitope mapped N-terminal region PSGL-1. examined effects early blockade in liver models cold ischemia, followed by ex vivo reperfusion or transplantation (orthotopic (OLT)) using an anti-PSGL-1 with diminished Fc-mediated effector function. In hepatic...
IL-13 contributes to airway hyperresponsiveness, mucus secretion, inflammation, and fibrosis, suggesting that it plays a central role in asthma pathogenesis. Neutralization of with sIL-13Ralpha2-Fc (sIL-13R) reduces allergen-induced responses rodent models respiratory disease, but its efficacy large animal model has not been previously reported. In this study, we determined whether two different strategies for neutralization modified experimental sheep. Sheep natural hypersensitivity Ascaris...
Interleukin (IL)-13 is a key cytokine driving allergic and asthmatic responses contributes to airway inflammation in cynomolgus monkeys after segmental challenge with <i>Ascaris suum</i> antigen. IL-13 bioactivity mediated by heterodimeric receptor (IL-13Rα1/IL-4Rα) can be inhibited vitro targeting interaction either chain. However, systems, neutralization activity may not always predict inhibitory function vivo. To address the efficacy of two different mechanisms primate model atopic...
The oncofetal protein, 5T4, is a tumor-associated protein displayed on the cell membrane of various carcinomas. This molecule promising target for anti-tumor vaccine development and targeted therapy with staphylococcus exotoxin. potential use 5T4 as antibody-guided chemotherapy has not been demonstrated. We report oncolytic efficacy selectivity in vitro vivo immuno-conjugates calicheamicin (CM) anti-5T4 antibody, H8. CM potent cytotoxic drug that causes double strand breaks DNA. Conjugates...
Structure and function of therapeutic antibodies can be modulated by a variety post-translational modifications (PTM). Tyrosine (Tyr) sulfation is type negatively charged PTM that occurs during protein trafficking through the Golgi. In this study, we discovered an anti-interleukin (IL)-4 human IgG1, produced transiently transfected HEK293 cells, contained fraction unusual species. Interestingly, isolated acidic species exhibited two-fold higher affinity to IL-4 nearly four-fold potency...
Abstract Next-generation site-specific cysteine-based antibody–drug-conjugates (ADCs) broaden therapeutic index by precise drug-antibody attachments. However, manufacturing such ADCs for clinical validation requires complex full reduction and reoxidation processes, impacting product quality. To overcome this technical challenge, we developed a novel antibody process through cysteine (Cys) metabolic engineering in Chinese hamster ovary cells implementing unique cysteine-capping technology....
Strong genetic data link the Tyrosine kinase receptor B (TrkB) and its major endogenous ligand brain-derived neurotrophic factor (BDNF) to regulation of energy homeostasis, with loss-of-function mutations in either gene causing severe obesity both mice humans. It has previously been reported that peripheral administration TrkB agonist neurotrophin-4 (NT-4) profoundly decreases food intake body weight rodents, while paradoxically increasing these same parameters monkeys. We generated a...
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,...
We report here the discovery and optimization of a novel T cell retargeting anti-GUCY2C x anti-CD3ε bispecific antibody for treatment solid tumors. Using combination hybridoma, phage display rational design protein engineering, we have developed fully humanized manufacturable CD3 that demonstrates favorable pharmacokinetic properties potent in vivo efficacy. Anti-GUCY2C antibodies derived from mouse hybridomas were first into well-behaved human variable region frameworks with full retention...
Abstract The hypothesis that amyloid beta peptides (Aβ) are central to the pathogenesis of sporadic Alzheimer’s disease (AD) is still hotly debated. Although several monoclonal antibodies (mAbs) against Aβ have failed in therapeutic clinical trials, two conformation-selective, anti-Aβ mAbs continue show promise. A significant challenge has been discover preferentially target protofibrils over natively-folded monomeric or plaques. We engineered a novel chaperone-like amyloid-binding protein...
Abstract Clinical use of vascular targeting antibody drug conjugates (VT-ADCs) has not yet been explored. Herein, we preclinically demonstrate utility, mechanisms and advantages VT-ADCs as targeted cancer therapeutics. A monoclonal human IgG1 selective for murine VEGFR2 (B3) is non-VEGF-A neutralizing traffics to the lysosome. B3 was conjugated a proprietary auristatin microtubule inhibitor with non-cleavable maleimidocaproyl linker, resulting in proof-of-concept VT-ADC, B3-mcMTI. In vitro,...
Abstract 5T4 (also known as TPBG) is a transmembrane, tumor-associated protein that rapidly internalizes. In preclinical models of NSCLC, was identified marker undifferentiated tumorigenic cells express properties tumor-initiating (TICs) and associated with highly proliferating (Ki67 positive) cell phenotype. addition, has been worse clinical outcome in NSCLC (Damelin et al, Cancer Res, 2011). We constructed an ADC humanized anti-5T4 Ab (A1) linked to the tubulin inhibitor...