A5017772219- Monoclonal and Polyclonal Antibodies Research
- Growth Hormone and Insulin-like Growth Factors
- Glycosylation and Glycoproteins Research
- PI3K/AKT/mTOR signaling in cancer
- Angiogenesis and VEGF in Cancer
- Cancer, Hypoxia, and Metabolism
- Chronic Lymphocytic Leukemia Research
- Phagocytosis and Immune Regulation
- TGF-β signaling in diseases
- Galectins and Cancer Biology
- Neuroendocrine Tumor Research Advances
- CAR-T cell therapy research
- Cell Adhesion Molecules Research
- Advanced Biosensing Techniques and Applications
- Metabolism, Diabetes, and Cancer
- Axon Guidance and Neuronal Signaling
- Immune cells in cancer
- Chronic Myeloid Leukemia Treatments
- Protein purification and stability
- Cerebrovascular and genetic disorders
- Cancer therapeutics and mechanisms
- Neuroblastoma Research and Treatments
- Congenital heart defects research
- Biosimilars and Bioanalytical Methods
- Lymphatic System and Diseases
Kaiser Permanente South San Francisco Medical Center
2014
Genentech
2004-2009
Molecular Oncology (United States)
2005
To fully assess the role of VEGF-A in tumor angiogenesis, antibodies that can block all sources vascular endothelial growth factor (VEGF) are desired. Selectively targeting tumor-derived VEGF overlooks contribution host stromal VEGF. Other strategies, such as receptors directly or using receptor decoys, result inhibiting not only but also homologues (e.g. placental factor, VEGF-B, and VEGF-C), which may play a angiogenesis. Here we report identification novel anti-VEGF antibodies, B20 G6,...
Colony stimulating factor 1 (CSF1) and interleukin 34 (IL34) signal via the CSF1 receptor to regulate macrophage differentiation. Studies in IL34- or CSF1-deficient mice have revealed that IL34 function is limited central nervous system skin during development. However, roles of at homeostasis context inflammatory diseases cancer wild-type not been clarified vivo. By neutralizing and/or adult mice, we identified they play important differentiation, specifically steady state microglia,...
In the quest to discover new research tools and develop better agents in fight against cancer, two antibodies, G6 B20-4, were isolated from synthetic antibody phage libraries. Unlike AVASTINtrade mark antibody, a recently approved agent for treatment of patients with colorectal B20-4 bind block both human murine vascular endothelial growth factor (VEGF). Here we have analyzed compared binding epitopes on VEGF these three antibodies using alanine-scanning mutagenesis structural analyses. The...
Transforming growth factor-β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions embryonic development; however, the postnatal pathological roles activation mechanisms TGFβ2 TGFβ3 not been well characterized. Here, we show that latent forms can be activated by integrin-independent lower thresholds compared to TGFβ1. Unlike TGFB1, TGFB2 TGFB3 expression increased human lung liver fibrotic tissues healthy control tissues....
Abstract Transforming growth factor β (TGFβ) signaling has been recently shown to reduce antitumor response PD-L1 blockade, leading a renewed enthusiasm in developing anti-TGFβ therapies for potential combination with cancer immunotherapy agents. Inhibition of TGFβ nonclinical toxicology species is associated serious adverse toxicities including cardiac valvulopathies and anemia. Previously, cardiovascular have thought be limited small molecule inhibitors receptor not considered liability...
BackgroundTransforming growth factor β (TGF-β) is implicated as a key mediator of pathological fibrosis, but its pleiotropic activity in range homeostatic functions presents challenges to safe and effective therapeutic targeting. There are three isoforms TGF-β, TGF-β1, TGF-β2, TGF-β3, which bind common receptor complex composed TGF-βR1 TGF-βR2 induce similar intracellular signals vitro. We have recently shown that the cellular expression patterns activation thresholds TGF-β2 TGF-β3 distinct...
Therapeutic antibody design is a complex multi-property optimization problem that traditionally relies on expensive search through sequence space. Here, we introduce "Lab-in-the-loop," paradigm shift for orchestrates generative machine learning models, multi-task property predictors, active ranking and selection, in vitro experimentation semi-autonomous, iterative loop. By automating the of variants, prediction, selection designs to assay lab, ingestion data, enable holistic, end-to-end...
The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years. Cytarabine- and anthracycline-based chemotherapy induction regimens (7 + 3) remain the standard care, most patients have poor long-term survival. reapproval Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), demonstrated ADCs as a clinically validated option to enhance effectiveness therapy. We are interested developing next-generation ADC for AML improve upon initial success...
B7-H4 has been implicated in cancers of the female reproductive system and investigated for its possible use as a biomarker cancer, but there are no preclinical studies to demonstrate that is molecular target therapeutic intervention cancer. We provide evidence prevalence expression levels high different subtypes breast cancer only few normal tissues express on cell membrane. These profiles low upregulation an opportunity antibody–drug conjugates (ADCs), cytotoxic drugs chemically linked...
Genetic polymorphisms in the region of trimeric serine hydrolase high-temperature requirement 1 (HTRA1) are associated with increased risk age-related macular degeneration (AMD) and disease progression, but precise biological function HtrA1 eye its contribution to etiologies remain undefined. In this study, we have developed an HtrA1-blocking Fab fragment test therapeutic hypothesis that protease activity is involved progression AMD. Next, generated activity-based small-molecule probe (ABP)...
To better understand how the relatively flat antigen-combining sites of antibodies interact with concave shaped substrate-binding clefts proteases, we determined structures two in complex trypsin-like hepatocyte growth-factor activator (HGFA). The inhibitory antibodies, Ab58 and Ab75, were generated from a human Fab phage display library synthetic diversity three complementarity determining regions (H1, H2, H3) heavy chain, mimicking natural Ig repertoire. Biochemical studies Fab58:HGFA...
Cell-cell communication in multicellular organisms depends on the dynamic and reversible phosphorylation of protein tyrosine residues. The receptor-linked phosphatases (RPTPs) receive cues from extracellular environment are well placed to influence cell signaling. However, direct events downstream these receptors have been challenging resolve. We report here that homophilic receptor PTPRK is stabilized at cell-cell contacts epithelial cells. By combining interaction studies, quantitative...
ABSTRACT Protein therapeutic design and property prediction are frequently hampered by data scarcity. Here we propose a new model, DyAb, that addresses these issues leveraging pair-wise representation to predict differences in protein properties, rather than absolute values. DyAb is built on top of pre-trained language model achieves Spearman rank correlation up 0.85 binding affinity across molecules targeting three different antigens (EGFR, IL-6, an internal target), given as few 100...
Abstract The transforming growth factor-β (TGFβ) cytokine family, which comprises three pleiotropic cytokines (TGFβ1, TGFβ2, and TGFβ3), plays a key role in many diseases including cancer fibrosis. of TGFβ disease is well established efforts to develop therapies via inhibition the isoforms their receptors have been pursued for decades. Unfortunately, progress this pursuit has limited as complete signaling pathway using small molecule inhibitors receptor or following administration potent...
Abstract The transforming growth factor-β (TGFβ) cytokine family, which comprises three pleiotropic cytokines (TGFβ1, TGFβ2, and TGFβ3), plays a key role in many diseases including cancer fibrosis. of TGFβ disease is well established efforts to develop therapies via inhibition the isoforms their receptors have been pursued for decades. Unfortunately, progress this pursuit has limited as complete signaling pathway using small molecule inhibitors receptor or following administration potent...