A5016696344- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Phagocytosis and Immune Regulation
- Microtubule and mitosis dynamics
- HER2/EGFR in Cancer Research
- Endoplasmic Reticulum Stress and Disease
- Lymphoma Diagnosis and Treatment
- Dermatology and Skin Diseases
- Cancer Research and Treatments
- Food Allergy and Anaphylaxis Research
- Immune cells in cancer
- Cell Adhesion Molecules Research
- Chronic Lymphocytic Leukemia Research
- Virus-based gene therapy research
- Transgenic Plants and Applications
- Cancer therapeutics and mechanisms
- Zebrafish Biomedical Research Applications
- Nanoplatforms for cancer theranostics
- Bladder and Urothelial Cancer Treatments
- NF-κB Signaling Pathways
- Neurobiology and Insect Physiology Research
Pfizer (United States)
2024-2025
Seagen (United States)
2016-2024
University of Colorado Denver
2004-2015
National Jewish Health
2004-2015
University of Colorado Anschutz Medical Campus
2014
University of Colorado Health
2005-2014
Howard Hughes Medical Institute
2005
Systemic lupus erythematosus (SLE) is characterized by high-avidity IgG antinuclear antibodies (ANAs) that are almost certainly products of T cell–dependent immune responses. Whether critical amino acids in the third complementarity-determining region (CDR3) ANA originate from V(D)J recombination or somatic hypermutation (SHM) not known. We studied a mouse model SLE which all mutations within V regions, including those CDR3, could be unequivocally identified. Mutation reversion analyses...
Abstract Brentuximab vedotin, a CD30-directed antibody–drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin monomethyl auristatin E (MMAE), highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment cancer cells with or free MMAE leads to catastrophic disruption the microtubule network eliciting robust endoplasmic reticulum (ER) stress response culminates...
Abstract We previously reported that selective ablation of certain γδ T cell subsets, rather than removal all cells, strongly affects serum Ab levels in nonimmunized mice. This type manipulation also changed including residual revealing some interdependence populations. For example, mice lacking Vγ4+ and Vγ6+ cells (B6.TCR-Vγ4−/−/6−/−), we observed expanded Vγ1+ which composition activation produced more IL-4 upon stimulation vitro, increased production by αβ as well spontaneous germinal...
Significance This study changes our understanding of the relationship between T cells and B cells. Although it is known that provide help for specific B-cell responses, unclear if to what extent also influence preimmune functions. We show here γδ modulate systemic antibody levels in nonimmunized mice, including all major subclasses especially IgE antibodies. One mouse strain deficient certain developed various autoantibodies, whereas mice had relatively normal Based on these other findings,...
Abstract PF-08046032 is a novel vedotin antibody-drug conjugate (ADC) engineered to target and deplete immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment (TME) through direct cytotoxicity. directs delivery of cytotoxic MMAE (monomethyl auristatin E) payload expressing CD25, alpha chain IL-2 receptor, which highly expressed on intratumoral Tregs lymphoma cells. The MMAE-based drug linker platform, utilized in four approved ADCs for hematologic solid tumors, has...
Abstract The checkpoint inhibitors anti-PD-1 and anti-CTLA-4 have been clinically successful as therapeutics for melanoma due to their ability reinvigorate the immune system. However, about half of patients do not benefit from these treatments, suggesting there are still barriers CD8+ T cell activation or infiltration into tumor microenvironment (TME). Additionally, while combination therapy (Ipilimumab-Nivolumab) improves response rate overall survival compared monotherapies, it also leads...
Abstract PF-08046037 (formerly known as SGN-PDL1iT) is an immune-stimulating antibody conjugate (ISAC) designed to induce immune response against cancer cells by delivering a potent Toll-like receptor 7 (TLR7) agonist tumor associated antigen-presenting (APCs) expressing PD-L1. The ISAC consists of anti-PD-L1 linked imidazoquinoline-based TLR7 using mannosidase-cleavable maleimidopropionyl-mannose linker (mp-mann). Upon binding PD-L1 on APCs, internalizes and releases the payload into...
Abstract Regulatory T cells (Tregs) are known to suppress antitumor immune responses and their presence in the tumor microenvironment (TME) is associated with cancer progression; therefore, Treg depletion a promising strategy enhance immunotherapy. PF-08046032 novel antibody-drug conjugate (ADC) designed target Tregs TME via CD25, alpha chain of IL-2 receptor frequently upregulated by intratumoral Tregs. composed an affinity-detuned anti-CD25 antibody linked monomethyl auristatin E (MMAE),...
We have developed a baculovirus-based display system for identifying antigen mimotopes MHC class I-specific T cells. The mouse I molecule, D d , was displayed on baculovirus-infected insect cells with library of 9- and 10-mer peptides tethered via flexible linker to the N terminus β2 microglobulin. As test case, screened by flow cytometry using multimeric fluorescent αβTCR from cell specific plus an unknown self peptide. A mimotope identified that, when bound stimulated secret IL-2. sequence...
The presence of multiple Na v 1 isotypes within a neuron and the lack specific blockers hamper identification in vivo roles sodium current ( I ) components, especially during embryonic stages. To identify functional properties components developing neurons, we took molecular genetic approach. Embryonic zebrafish Rohon–Beard (RB) mechanosensory neurons express two different channel isotypes: 1.1 1.6. examine 1.1- 1.6-encoded currents RB cells at developmental stages, eliminated contribution...
Abstract Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate (ADC) directed against CD30. This ADC consists of monoclonal antibodies conjugated to the auristatin monomethyl E (MMAE) a microtubule-disrupting agent. antitumor activity thought be primarily result intracellular payload release leading mitotic arrest and apoptotic cell death. We have recently demonstrated that brentuximab induces surface expression calreticulin HSP70 as well activation transcription factor ATF6 which...
Antibody diversity creates an immunoregulatory challenge for T cells that must cooperate with B cells, yet discriminate between self and nonself. To examine the consequences of cell reactions to receptor (BCR), we generated a transgenic (Tg) line mice expressing (TCR) specific κ variable region peptide in monoclonal antibody (mAb) 36-71. The epitope was originally by pair somatic mutations arose naturally during immune response. By crossing this TCR Tg mouse chain mAb 36-71, found κ-specific...
<h3>Background</h3> Enfortumab vedotin (EV) is a first-in-class Nectin-4-directed antibody-drug conjugate (ADC) with demonstrated improved overall survival in patients previously treated advanced-stage urothelial carcinoma.<sup>1</sup> EV comprised of fully human monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) by protease cleavable maleimidocaproyl-valine-citrulline linker. has multifaceted mechanism action. Previously, we that induces...
Linked recognition of Ag by B and T lymphocytes is ensured in part a state tolerance acquired CD4 cells to germline-encoded sequences within the cell receptor (BCR). We sought determine how such attained when peptide from BCR variable (V) region expressed small numbers as it physiological state. Mixed bone marrow (BM) chimeras were generated using donor BM mice with that transgene (Tg)-encoded κ L chain TCR Tg which (CA30) specific for Vκ encoded κTg. In where few express κTg, many CA30...
Abstract Brentuximab vedotin (BV) is an antibody-drug conjugate directed against CD30 consisting of a monoclonal antibody conjugated to monomethyl auristatin E (MMAE), microtubule-disrupting agent. BV antitumor activity thought be primarily the result intracellular payload release leading mitotic arrest and apoptotic cell death. We have demonstrated that drives apoptosis in manner consistent with immunogenic death (ICD) including activation unfolded protein/ER stress response concomitant...
A fundamental problem in immunoregulation is how CD4(+) T cells react to immunogenic peptides derived from the V region of BCR that are created by somatic mechanisms, presented MHC II, and amplified abundance B cell clonal expansion during immunity. neo Ags open a potentially dangerous avenue help violation principle linked Ag recognition. To analyze this issue, we developed murine adoptive transfer model using paired donor CD4 specific for BCR-derived peptide. peptide-specific aborted...
Abstract SGN-2FF, an orally bioavailable small molecule inhibitor of glycoprotein fucosylation, demonstrates encouraging preclinical antitumor activity in mouse models with suggested multiple mechanisms action, including direct and indirect effects on immune cells, tumor the microenvironment. The SGN-2FF were evaluated tumors implanted strains mice to determine how differences repertoire affect activity. treatment nude mice, which maintain functional B cells antibody production, resulted a...
Autoreactive anergic B lymphocytes are considered to be dangerous because of their potential for activation and recruitment into autoimmune responses. However, they persist days constitute ∼5% the cell pool. We assessed functional in Ars/A1 transgene model, where cells express a dual-reactive Ag receptor that binds, addition self-Ag, hapten p-azophenylarsonate (Ars). When were transferred adoptive recipients immunized with foreign proteins covalently conjugated Ars, endogenous IgG immune...
Abstract Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) directed against CD30, a TNF receptor superfamily (TNFRSF) member highly expressed on Reed Sternberg cells in Hodgkin lymphoma (HL) and also commonly number of other lymphoid malignancies such as ALCL CTCL. BV consists monoclonal antibody conjugated to monomethyl auristatin E (MMAE), potent microtubule-disrupting agent. MMAE-based ADC antitumor activity primarily results from intracellular payload release, leading mitotic...
Abstract Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis by preventing excessive inflammation normal tissues. In cancer, Tregs hamper antitumor immunosurveillance and may be a resistance mechanism to anti-PD-1 therapies. preclinical cancer models, Treg depletion enhances cytotoxic responses, but systemic persistent removal can elicit immunopathology. Therapeutic strategies that selectively deplete highly suppressive activated intratumoral avoid...
TIGIT is an immune checkpoint receptor expressed on activated and memory T cells, immunosuppressive regulatory natural killer (NK) cells. has emerged as attractive target for antitumor therapies, due to its proposed effects lymphocyte function cell activation. We generated anti-TIGIT monoclonal antibody (mAb) that binds with high affinity human, non-human primate, murine through multiple experimental methodologies demonstrated blockade alone insufficient activity. Generating mAbs various Fc...
Abstract Agonist antibodies targeting 4-1BB (CD137) effectively costimulate cytotoxic T cells and are active in preclinical models of cancer. However, the clinical development these agents has been hampered by limited efficacy and/or poor tolerability at doses. To overcome safety limitations this approach, SGN-BB228, a first-in-class, investigational CD228 × costimulatory Antibody Anticalin® bispecific (MabcalinTM) was created. SGN-BB228 is designed to target (melanotransferrin),...