A5037257713- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Monoclonal and Polyclonal Antibodies Research
- Cancer Research and Treatments
- Chronic Lymphocytic Leukemia Research
- Pancreatic and Hepatic Oncology Research
- Immunotherapy and Immune Responses
- Occupational and environmental lung diseases
- Cell Adhesion Molecules Research
- Phagocytosis and Immune Regulation
- Immune Cell Function and Interaction
- Ion Channels and Receptors
- Glycosylation and Glycoproteins Research
- Herbal Medicine Research Studies
- Diabetes Treatment and Management
- Respiratory and Cough-Related Research
- CRISPR and Genetic Engineering
- Lung Cancer Research Studies
- Nanowire Synthesis and Applications
- Prostate Cancer Treatment and Research
- Peptidase Inhibition and Analysis
- Genomics and Rare Diseases
- Skin and Cellular Biology Research
- Multiple Myeloma Research and Treatments
- Bioactive Compounds and Antitumor Agents
Rapt Therapeutics (United States)
2023-2024
Boston Children's Museum
2024
Boston Children's Hospital
2024
University of California, San Diego
2014-2016
Amgen (United States)
2012
E-Phy-Science (France)
2009
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) by interacting with the receptor (LDLR) and is an attractive therapeutic target for LDL-C lowering. We have generated a neutralizing anti-PCSK9 antibody, mAb1, that binds to epitope on PCSK9 adjacent region required LDLR interaction. In vitro, mAb1 inhibits binding attenuates PCSK9-mediated reduction in protein levels, thereby increasing uptake. A combination of statin increases levels HepG2 cells...
Transient receptor potential ankyrin-1 (TRPA1) and transient vanilloid-1 (TRPV1) are calcium (Ca2+)-permeable ion channels mostly known as pain receptors in sensory neurons. However, growing evidence suggests their crucial involvement the pathogenesis of IBD. We explored possible contribution TRPA1 TRPV1 to T-cell-mediated colitis.We evaluated role Trpa1 gene deletion two models experimental colitis (ie, interleukin-10 knockout T-cell-adoptive transfer models). performed electrophysiological...
Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs clinical efficacy with MSLN-targeting agents have validated MSLN as promising target for therapeutic intervention, but therapies improved are still needed to address the significant unmet medical need posed by MSLN-expressing cancers.We designed HPN536, 53-kDa, trispecific, T-cell-activating...
Abstract T cells have a unique capability to eliminate cancer and fight malignancies. Cancer adopted multiple immune evasion mechanisms aimed at inhibiting cells. Dramatically improved patient outcomes been achieved with therapies genetically reprogramming cells, blocking T-cell inhibition by or transiently connecting for redirected lysis. This last modality is based on antibody constructs that bind surface antigen an invariant component of the receptor. Although high response rates were...
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Abstract HPN328: An Anti-DLL3 T Cell Engager for Treatment of Small Lung Cancer Delta-like protein 3 (DLL3) is a Notch inhibitory ligand expressed in more than 70% small cell lung cancers (SCLCs), while there little to no surface expression normal adult tissues outside the CNS *1. SCLC an aggressive neuroendocrine tumor that represents about 15 percent all cancers. Although often responsive standard care treatment, relapse common, with median progression-free survival 2–3 months and overall...
Abstract Metastatic, castrate-resistant prostate cancer (mCRPC) is diagnosed in up to 50,000 patients each year the US alone, and roughly 27,000 will succumb it every year. Once metastasized beyond regional lymph nodes, 5-year survival rate 30%. While novel therapeutics like abiraterone enzalutamide have improved treatment options for mCRPC, no curative available, new therapies are urgently needed. HPN424 a ~50-kDa antibody derivative called TriTAC (Tri-specific T cell Activating Construct)...
Abstract Mesothelin (MSLN) is a GPI-linked tumor antigen overexpressed in variety of solid tumors, including ovarian, pancreatic, lung and triple-negative breast cancer. Normal tissue expression restricted to single-cell, mesothelial layers lining the pleural, pericardial, peritoneal cavities. Overexpression MSLN associated with poor prognosis adenocarcinoma has been used as cancer target for numerous modalities, immunotoxins, vaccines, antibody drug conjugates CAR-T cells. Early signs...
Abstract T cell engagers are antibody-based therapeutics that transiently tether cells via the receptor complex (TCR) to surface antigens on tumor cells. This leads activation of and redirected lysis attached target cell. The therapeutic potential this modality was demonstrated by blinatumomab, a CD19/CD3-bispecific engager approved for treatment adult patients with relapsed/refractory acute lymphoblastic leukemia. Despite success cell-engaging therapy in hematologic malignancy, clinical...
<h3>Background</h3> CD3-targeted T cell engagers are potent anti-tumor therapies, but their development often requires management of cytokine release syndrome (CRS). Subcutaneous dosing is a promising strategy to reduce CRS, its application limited by increased immunogenicity risks. hypothesized mitigate CRS reducing the maximum drug concentration (Cmax) and preserve efficacy maintaining same minimum (Cmin) as intravenous dosing. A engager designed be dosed intravenously engineered mimic PK...
Abstract Tumor-associated calcium signal transducer 2 (Trop2) is a cell surface glycoprotein that promotes renewal, proliferation and tumorigenesis. Trop2 homogenously overexpressed in numerous solid tumor types, including breast, head neck, prostate, bladder, non-small carcinoma; however, also expressed several normal tissues, skin, respiratory tract, female reproductive organs. Although Trop2-targeted antibody drug conjugates (ADCs) have demonstrated clinical activity, with regulatory...
Abstract T cell engagers have compelling clinical activity, but their use is limited by the availability of tumor targets with minimal normal tissue expression. Conditionally active designed to be only in and spare tissues could increase number addressable targets. Here, we describe a engager prodrug platform, named ProTriTAC, that preferentially reduce its on-target/off-tumor toxicity improve safety profile targeting solid antigens. ProTriTACs are based on TriTAC platform three binding...
Abstract Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC highly aggressive, limited therapeutic options lead to poor prognosis for patients. HPN328 a trispecific T cell–activating construct (TriTAC) consisting three binding domains: CD3 binder T-cell engagement, an albumin half-life extension, DLL3 engagement. In vitro assays, rodent models, non-human primates were used assess the activity HPN328....
<p>TriTAC mediated cytotoxic activity in vitro and vivo the hCD3ε mouse model.</p>
<p>IHC staining of NCI-H82 xenograft tumors.</p>
<div>Abstract<p>Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC highly aggressive, limited therapeutic options lead to poor prognosis for patients. HPN328 a trispecific T cell–activating construct (TriTAC) consisting three binding domains: CD3 binder T-cell engagement, an albumin half-life extension, DLL3 engagement. <i>In vitro</i> assays, rodent models, non-human primates...
<p>HPN328 binding selectivity to human DLL1 and DLL4.</p>
<p>Stimulation with anti-human CD3 and anti-mouse CD28 beads induces proliferation activation of T cells from hCD3ε mice.</p>
<p>Structure of HPN328.</p>
<p>TDCC co-cultures show no secretion of cytokines in the presence DLL3 negative tumor cell line.</p>
<p>IHC staining of NCI-H82 xenograft tumors.</p>
<p>HPN328 binds to the MC38-hDLL3 cell line.</p>