A5079288943- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Advanced Biosensing Techniques and Applications
- Radiopharmaceutical Chemistry and Applications
- Cancer Immunotherapy and Biomarkers
- Estrogen and related hormone effects
- Glycosylation and Glycoproteins Research
- Cytokine Signaling Pathways and Interactions
- Angiogenesis and VEGF in Cancer
- Viral-associated cancers and disorders
- Cytomegalovirus and herpesvirus research
- Computational Drug Discovery Methods
- Cell Adhesion Molecules Research
- Click Chemistry and Applications
- vaccines and immunoinformatics approaches
- Advanced Breast Cancer Therapies
- Lymphoma Diagnosis and Treatment
- Heat shock proteins research
- Congenital heart defects research
- Cancer Cells and Metastasis
- Redox biology and oxidative stress
- Metal complexes synthesis and properties
- Peptidase Inhibition and Analysis
Regeneron (United States)
2016-2025
Synta Pharmaceuticals (United States)
2007-2023
GlaxoSmithKline (United States)
2023
Harvard University
2005
Howard Hughes Medical Institute
1995-2001
University of California, San Francisco
1995-2000
In this study we examine the molecular basis for synergistic regulation of minimal TCR alpha enhancer by multiple proteins. We find that reconstitution function in nonlymphoid cells requires expression lymphoid-specific proteins LEF-1, Ets-1 and PEBP2 (CBF alpha), a specific arrangement their binding sites enhancer. show cooperates with to bind adjacent at one end enhancer, forming ternary complex is unstable itself. Stable occupancy Ets-1- alpha-binding DNase I protection assay was found...
ABSTRACT Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is a lymphotropic virus strongly linked to the development of KS, an endothelial cell neoplasm frequent in persons with AIDS. Reactivation from latency B cells thought be important antecedent viral spread during KS pathogenesis. Earlier experiments have posited role for transcriptional activator encoded by KSHV open reading frame 50 (ORF50) such reactivation, since ectopic overexpression this protein induces reactivation latently...
Abstract Elesclomol (formerly STA-4783) is a novel small molecule undergoing clinical evaluation in pivotal phase III melanoma trial (SYMMETRY). In II randomized, double-blinded, controlled, multi-center 81 patients with stage IV metastatic melanoma, treatment elesclomol plus paclitaxel showed statistically significant doubling of progression-free survival time compared alone. Although displays therapeutic activity the clinic, mechanism underlying its anticancer has not been defined...
Bispecific antibodies, while showing great therapeutic potential, pose formidable challenges with respect to their assembly, stability, immunogenicity, and pharmacodynamics. Here we describe a novel class of bispecific antibodies native human immunoglobulin format. The design exploits differences in the affinities isotypes for Protein A, allowing efficient large-scale purification. Using this format, generated antibody, REGN1979, targeting B cell marker, CD20, CD3 component T receptor, which...
The properties of cell surface proteins targeted by antibody-drug conjugates (ADCs) have not been fully exploited; particular importance are the rate internalization and route intracellular trafficking. In this study, we compared trafficking HER2, which is target clinically approved ADC ado-trastuzumab emtansine (T-DM1), with that prolactin receptor (PRLR), another potential in breast cancer. contrast to found PRLR rapidly constitutively internalized, traffics efficiently lysosomes, where it...
Tumor angiogenesis is an important target for cancer therapy, with most current therapies designed to block the VEGF signaling pathway. However, clinical resistance anti-VEGF therapy highlights need targeting additional tumor pathways. The endothelial Notch ligand Dll4 (delta-like 4) has recently emerged as a critical regulator of and thus promising new therapeutic anti-angiogenesis target. Blockade Dll4-Notch in tumors results excessive, non-productive resultant inhibitory effects on...
A CD3 bispecific antibody targeting Mucin 16 shows preclinical efficacy in mouse tumor models and a tolerable safety profile nonhuman primates.
CD28 bispecific antibodies are well tolerated and enhance the antitumor efficacy of CD3 bispecifics as a potential off-the-shelf antibody therapy.
Abstract T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind T cells via CD3 and tumor tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing cells. The promising preclinical clinical efficacy TSAxCD3 is often accompanied by toxicities such cytokine release syndrome due T-cell activation. How the toxicity profile depends on binding affinity remains unclear. Here, we evaluate that were engineered range...
ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus-8) establishes latent and lytic infections in both lymphoid endothelial cells has been associated with diseases of cell types. The KSHV open reading frame 50 (ORF50) protein is a transcriptional activator that plays central role the reactivation viral replication from latency. Here we identify characterize DNA binding site for ORF50 shared by promoters two delayed early genes (ORF57 K-bZIP). Transfer this...
ABSTRACT Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) encodes a G-protein-coupled receptor (GCR) homolog. This protein is potent, constitutively active signalling molecule that can influence both proliferation and angiogenesis when ectopically expressed in fibroblasts vitro. Here we have examined the expression of KSHV GCR gene virus-infected lymphoid cells KS tumors. Our results show situations primarily during lytic replication; its transcription unaffected by inhibition viral DNA...
ABSTRACT Open reading frame (ORF) 57 of Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a homolog known posttranscriptional regulators that are essential for replication in other herpesviruses. Here, we examined the expression this gene and function(s) its product. KSHV ORF is expressed very early infection from 1.6-kb spliced RNA bearing several in-frame initiation codons. Its product nuclear protein that, transient assays, has little effect on luciferase reporter genes driven by...
CD3-engaging bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells are potent therapeutic approaches for redirecting patient to recognize kill tumors. Here we describe a fully human bsAb (REGN5458) that binds B-cell maturation (BCMA) CD3, compare its antitumor activities vs those of anti-BCMA CAR identify differences in efficacy mechanism action. In vitro, BCMAxCD3 efficiently induced polyclonal T-cell killing primary plasma multiple myeloma (MM) cell lines expressing...
Abstract The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), fully human IgG1 monoclonal antibody that binds with sub-nanomolar affinity inhibits signaling. Administering to immunodeficient mice engineered express inhibited growth several xenografts...
Abstract Patients with hematologic cancers have improved outcomes after treatment bispecific antibodies that bind to CD3 on T cells and redirect toward cancer cells. However, clinical benefit against solid tumors remains be shown. We made a antibody targets both the common prostate tumor–specific antigen PSMA (PMSAxCD3) provide evidence for tumor inhibition in several preclinical models. Mice expressing human extracellular regions of were generated examine antitumor efficacy presence an...
Background Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blocking antibodies including cemiplimab have generated profound clinical activity across diverse cancer types. Tumorous PD-L1 expression, as assessed by immunohistochemistry (IHC), is an accepted predictive marker of response to therapy in some cancers. However, expression often dynamic and heterogeneous, therefore not reliably captured IHC from tumor biopsies or archival samples. Thus, there significant need...
TPS295 Background: mCRPC is characterized by an immunosuppressive tumor microenvironment with few intratumoral effector T cells, leading to low response rates immune checkpoint inhibitors; therefore, novel immunotherapy approaches are needed. Prostate-specific membrane antigen (PSMA) highly expressed in malignant prostate cancer cells. REGN4336 a PSMA×CD3 bispecific antibody (bsAb) that facilitates T-cell–mediated killing bridging PSMA-expressing cells CD3+T providing “signal 1” for T-cell...
Monoclonal antibody therapies have transformed the lives of patients across a diverse range diseases. However, antibodies can usually only access extracellular proteins, including portions membrane proteins that are expressed on cell surface. In contrast, T receptors (TCRs) survey entire cellular proteome when processed and presented as peptides in association with human leukocyte antigen (pHLA complexes). Antibodies mimic TCRs by recognizing pHLA complexes potential to extend reach this...
ABSTRACT Interferon production and apoptosis in virus-infected cells are necessary to prevent progeny virus eliminate infected cells. Paramyxovirus infection induces through interferon regulatory factor 3 (IRF-3), but the exact mechanism of how IRF-3 functions is unknown. We show that involved transcriptional induction TRAIL, a key player pathway. upregulates TRAIL transcription following viral binds an interferon-stimulated response element promoter. The mRNA for its receptor, DR5, induced...
The Prolactin Receptor (PRLR) is a type 1 cytokine receptor that expressed in subset of breast cancers and may contribute to its pathogenesis. It relatively overexpressed approximately 25% human tumors while at low levels some normal tissues including the mammary gland. We developed an anti-PRLR antibody-drug conjugate (ADC), target PRLR-positive cancer. REGN2878-DM1 comprised fully high-affinity function-blocking IgG1 antibody (REGN2878) conjugated via noncleavable SMCC linker cytotoxic...
512 Background: OF causes accelerated bone loss in premenopausal women receiving AdC of greater magnitude than natural menopause or aromatase inhibitor therapy postmenopausal women. CALGB 79809 compared the effect early ZA (with AdC) late (one year after on change BMD lumbar spine (LS). We report versus no (Control) at 12 months randomization. Methods: Eligible (≥ 40 years; stages I-III breast cancer; and last menstrual period ≤ 6 prior to entry) were randomized either 4 mg IV every 3...
Abstract The essential role of the Delta‐like ligand 4 (Dll4)‐Notch signaling pathway in T‐lymphocyte development is well established. It has been shown that specific inactivation Dll4 on thymic stromal cells during early post‐natal leads to a deregulation T‐cell differentiation. However, whether ongoing Dll4‐Notch required for adult thymus unknown. use anti‐Dll4 Abs allowed us confirm and expand previous studies by examining kinetics reversibility blockade mice. We found treatment reduced...