A5029113634- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- HER2/EGFR in Cancer Research
- Glycosylation and Glycoproteins Research
- Cell Adhesion Molecules Research
- T-cell and B-cell Immunology
- Lymphoma Diagnosis and Treatment
- Chronic Lymphocytic Leukemia Research
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- Phagocytosis and Immune Regulation
- Multiple Myeloma Research and Treatments
- Radiopharmaceutical Chemistry and Applications
- Cancer Research and Treatments
- Advanced Biosensing Techniques and Applications
- Galectins and Cancer Biology
- Microtubule and mitosis dynamics
- Immune cells in cancer
- Immunodeficiency and Autoimmune Disorders
- Acute Myeloid Leukemia Research
- Pancreatic and Hepatic Oncology Research
- Platelet Disorders and Treatments
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Protein Degradation and Inhibitors
Seagen (United States)
2009-2023
Rapt Therapeutics (United States)
2023
Seagen (Canada)
2009-2016
Children's Hospital of Philadelphia
2014
Molecular Oncology (United States)
2006-2008
Dana-Farber Cancer Institute
2006
Cornell University
2005
University of Washington
1992-1999
Seattle University
1996
University of Washington Medical Center
1995-1996
Antibody-drug conjugates (ADC) comprise targeting antibodies armed with potent small-molecule payloads. ADCs demonstrate specific cell killing in clinic, but the basis of their antitumor activity is not fully understood. In this study, we investigated degree to which payload release predicts ADC vitro and vivo were generated target different receptors on anaplastic large lymphoma line L-82, delivered same cytotoxic (monomethyl auristatin E, MMAE), found that intracellular concentration...
A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, engineered at position 239 of heavy chains. The h1F6239C-PBD conjugation strategy proved be superior cysteine conjugation, affording an antibody-drug conjugate (ADC) high uniformity in drug-loading and low levels aggregation. In vitro cytotoxicity experiments demonstrated...
The chimeric anti-CD30 monoclonal antibody cAC10, linked to the antimitotic agents monomethyl auristatin E (MMAE) or F (MMAF), produces potent and highly CD30-selective anti-tumor activity in vitro vivo. These drugs are appended via a valine-citrulline (vc) dipeptide linkage designed for high stability serum conditional cleavage putative release of fully active by lysosomal cathepsins. To characterize biochemical processes leading effective drug delivery, we examined intracellular...
Abstract TCR stimulation results in the tyrosine phosphorylation of a number cellular substrates. We have recently identified 70-kDa protein kinase, ZAP-70, which associates with human zeta-chain after stimulation. report here isolation and sequence cDNA clone that encodes murine ZAP-70. Murine ZAP-70 share 93% amino acid identity are homologous to 72-kDa kinase Syk. Syk has been implicated signal transduction pathways B cell membrane Ig high affinity IgE receptors, Fc epsilon RI. In...
Stimulation of platelets by the extracellular matrix protein collagen leads to activation a tyrosine kinase-dependent mechanism resulting in secretion and aggregation. Tyrosine phosphorylation kinase Syk phospholipase Cγ2 are early events collagen-induced activation. We recently proposed that collagen-signaling involves receptor or receptor-associated containing an immunoreceptor tyrosine-based motif (ITAM) enabling interaction with Syk. In this report we show stimulation causes rapid ITAM...
Antigen receptor ligation on lymphocytes activates protein tyrosine kinases and phospholipase C-␥ (PLC-␥) isoforms.Glutathione S-transferase fusion proteins containing the C-terminal Src-homology 2 [SH2(C)] domain of PLC-␥1 bound to tyrosyl phosphorylated Syk.Syk isolated from antigen receptor-activated B cells Tyr-771 key regulatory residue Tyr-783 in vitro, whereas Lyn same only Tyr-771.The ability Syk phosphorylate required ligation, while was constitutively active.An mCD8-Syk cDNA...
Cross-linking B cell antigen receptor (BCR) elicits early signal transduction events, including activation of protein tyrosine kinases, phosphorylation components, phospholipase C-gamma (PLC-gamma), and increases in intracellular free Ca2+. In this article, we report that cross-linking the BCR led to a rapid translocation cytosolic phosphatase (PTP) 1C particulate fraction, where it became associated with 140-150-kD tyrosyl-phosphorylated protein. Western blotting analysis identified be...
The key role played by fucose in glycoprotein and cellular function has prompted significant research toward identifying recombinant biochemical strategies for blocking its incorporation into proteins membrane structures. Technologies surrounding engineered cell lines have evolved the inhibition of vitro fucosylation, but they are not applicable vivo use drug development. To address this, we screened a panel analogues identified 2-fluorofucose 5-alkynylfucose derivatives that depleted cells...
Abstract Changes in T cell helper function were analyzed when anti-CD3-activated cells costimulated with mAbs to the CD28 receptor (anti-CD28). cell-dependent B growth and differentiation consistently augmented if anti-CD3 stimulated-T simultaneously activated anti-CD28. Although anti-CD28 enhanced IL-2 IL-4 production, it did not increase responses solely by augmenting production of soluble lymphokines. Anti-CD28 costimulation induced increases on CD40 ligand (CD40L), known promote...
Activation of human platelets by cross-linking the platelet low-affinity IgG receptor, Fc gamma receptor IIA (Fc gamma-RIIA), or collagen is associated with rapid phosphorylation on tyrosine non-receptor kinase syk. Phosphorylation still observed, albeit sometimes reduced, in presence a combination protein C inhibitor, Ro 31-8220, and intracellular calcium chelator, BAPTA-AM, demonstrating independence from phosphoinositide-specific phospholipase (PLC) activity. In contrast, 31-8220 BAPTA-AM...
B cell antigen receptors are multicomponent complexes consisting of the surface immunoglobulin and accessory molecules with associating protein-tyrosine kinases. A spleen tyrosine kinase, Syk, in porcine cells a 72-kDa PTK72, murine associate receptor. Herein, we report isolation full-length cDNA encoding human homologue Syk. This predicted polypeptide two NH2-terminal SH2 domains COOH-terminal kinase domain. Syk is highly conserved between swine homologous to T cell-associated ZAP-70. Both...
Antibody-drug conjugates (ADCs) made with auristatin antimitotic agents have shown significant preclinical and clinical oncology activity. SGN-75 is composed of the anti-CD70 antibody h1F6 conjugated to monomethylauristatin F through a noncleavable maleimidocaproyl linkage. To understand pharmacologic basis activity this ADC, its pharmacokinetics biodistribution were evaluated in mouse xenograft model use dual-radiolabeled ADC. The concentrations antibody, total (conjugated plus...
SGN-40 is a humanized IgG1 antihuman CD40 that currently in phase I clinical trial for the treatment of multiple myeloma. As surface expression on B-lineage cells maintained from pro-B to plasma cells, may be applicable other B-cell neoplasias, including non-Hodgkin's lymphoma. In this study, we examined potential vitro and vivo anti-B-lineage lymphoma activity SGN-40. Recombinant was expressed purified Chinese hamster ovary characterized based binding affinity, specificity, normal...
Increased expression of CD30 is associated with a variety hematologic malignancies, including Hodgkin disease (HD) and anaplastic large cell lymphoma (ALCL). The anti-CD30 monoclonal antibody SGN-30 induces direct antitumor activity by promoting growth arrest DNA fragmentation CD30+ tumor cells. In this study, we investigated the contributions Fc-mediated effector functions to activity. We determined that antibody-dependent cellular phagocytosis, mediated macrophages, contribute...
Propagation of signals from the T cell antigen receptor (TCR) involves a number adaptor molecules. SH2 domain–containing protein 76 (SLP-76) interacts with guanine nucleotide exchange factor Vav to activate nuclear activated cells (NF-AT), and its expression is required for normal development. We report cloning characterization novel Grb2-like molecule designated as Grb2-related lymphoid system (GrpL). Expression GrpL restricted hematopoietic tissues, it distinguished Grb2 by having...
Abstract The anti-CD20 antibody rituximab is useful in the treatment of certain B-cell malignancies, most notably non-Hodgkin’s lymphoma. Its efficacy has been increased when used combination with chemotherapy, yet monoclonal antibodies (mAbs) directly conjugated drugs such as doxorubicin (Dox) have failed to deliver drug or demonstrate antitumor activity. We produced antibody-drug conjugates that possess potent activity by using anti-mitotic agent, monomethyl auristatin E (MMAE), linked via...
The human B lymphocyte-specific Ag, CD22, is a cell adhesion molecule expressed on the surface during narrow window of development, coincident with IgD. A ligand for CD22 has recently been identified T cells as low molecular mass isoform leukocyte common CD45RO. reported to function in regulation both and activation vitro. In this study, we report isolation expression cDNA clone encoding murine homologue mCD22. Within their predicted protein sequences, sequences overall have 62% identity,...
Abstract The absence of long term bone marrow cultures for studying the growth and differentiation human B cell precursors (BCP) has placed restrictions on ability to analyze early stages ontogeny. We now describe a marrow-derived adherent microenvironment that maintains BCP several weeks in vitro. cells are maintained serum-free tissue culture medium, consist predominant population CD10+ fibroblast-like minor CD10+/nonspecific esterase+ macrophages. Adherent seeded with fresh or...
CD70 (CD27L) is a member of the tumor necrosis factor family aberrantly expressed on number hematologic malignancies and some carcinomas. expression malignant cells coupled with its highly restricted normal makes an attractive target for monoclonal antibody (mAb)-based therapies. We developed humanized anti-CD70 antibody, SGN-70, herein describe antitumor activities this mAb.CD70 primary tumors was evaluated by immunohistochemical staining Hodgkin lymphoma, non-Hodgkin multiple myeloma,...