A5038520217- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Immunotherapy and Immune Responses
- Axon Guidance and Neuronal Signaling
- Glycosylation and Glycoproteins Research
- Immune Cell Function and Interaction
- Cell Adhesion Molecules Research
- Cancer Immunotherapy and Biomarkers
- T-cell and B-cell Immunology
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Cancer-related Molecular Pathways
- Lung Cancer Research Studies
- Angiogenesis and VEGF in Cancer
- Nanoparticle-Based Drug Delivery
- Advanced Biosensing Techniques and Applications
- Microtubule and mitosis dynamics
- Cancer therapeutics and mechanisms
- Synthesis and biological activity
- Toxin Mechanisms and Immunotoxins
- Immune Response and Inflammation
- interferon and immune responses
- DNA Repair Mechanisms
- Radiopharmaceutical Chemistry and Applications
- Liver Diseases and Immunity
Merrimack Pharmaceuticals (United States)
2009-2020
Massachusetts Eye and Ear Infirmary
2006
Smith-Kettlewell Eye Research Institute
2006
Harvard University
2004
Boston University
2004
The prevalence of ErbB2 amplification in breast cancer has resulted the heavy pursuit as a therapeutic target. Although both monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success clinic, many patients fail to benefit. In addition, majority who initially respond will unfortunately ultimately progress on these therapies. Activation ErbB3, preferred dimerization partner ErbB2, plays key role driving ErbB2-amplified tumor growth, but we found that...
Structure−activity relationship studies of substituted arylsulfoanilides as antiproliferatives, which are mediated by the partial depletion intracellular Ca2+ stores, resulted in identification compounds with micromolar activity against lung cancer cells a growth inhibition assay. Incorporating substitution pattern best onto 3-phenyloxindole scaffold potent arylsulfoanilide−oxindole hybrid, 27. Compound 27 inhibits cell stores and phosphorylation eIF2α.
Anti-TNFR2 antibodies induce costimulation of T cells, complete tumor regression, and immune memory in mice can be combined with anti-PD1.
CD137 (4-1BB) is a co-stimulatory receptor on immune cells and Nectin-4 cell adhesion molecule that overexpressed in multiple tumor types. Using series of poly(ethylene glycol) (PEG)-based linkers, synthetic bicyclic peptides targeting were conjugated to Bicycles Nectin-4. The resulting bispecific molecules potent agonists require the presence both Nectin-4-expressing CD137-expressing for activity. A multipronged approach was taken optimize these Bicycle tumor-targeted by exploring impact...
Human acquired enamel pellicle is formed by molecules selectively adsorbed onto tooth surfaces. The present work describes the use of monoclonal antibody (mAb) technology as a novel approach to identify micro amounts components in pellicle. MAbs were obtained with reactivities against statherin, histatin, mucous glycoprotein 1(MGI), albumin, amylase and human immunoglobulins (Igs), indicating that these are components, which was further confirmed immunoblotting. No mAbs proline-rich proteins...
Abstract Combinations of chemotherapy with immunotherapy have seen recent clinical success, including two approvals anti–PD-1/L1 agents in combination taxane-based non–small cell lung cancer and triple-negative breast cancer. Here, we present a study on the activity mechanistic rationale novel EphA2-targeted liposomal taxane (EphA2-ILs-DTXp) anti–PD-1. This was highly active mouse syngeneic tumor models, complete responses observed 3 5 models. In EMT-6 model, EphA2-ILs-DTXp anti–PD-1...
Ephrin receptor A2 (EphA2) is a member of the Ephrin/Eph cell-to-cell signaling family molecules, and it plays key role in cell proliferation, differentiation, migration. EphA2 overexpressed broad range cancers, its expression many cases associated with poor prognosis. We recently developed novel EphA2-targeting antibody-directed nanotherapeutic encapsulating labile prodrug docetaxel (EphA2-ILs-DTXp) for treatment EphA2-expressing malignancies. Here, we characterized bladder cancer using...
Abstract Administration of a novel and selective small molecule integrin αvβ6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction epithelial proliferative changes urinary bladder 2 animals, absence test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae cells, variable cytologic atypia, high mitotic rate, without invasion into tunica muscularis. Morphologic features patterns tumor growth...
Inhibition of integrin αvβ6 is a promising approach to the treatment fibrotic disease such as idiopathic pulmonary fibrosis. Screening small library combining head groups that stabilize bent-closed conformation αIIbβ3 with αv binding motifs resulted in identification hit compounds bind αvβ6. Crystal structures these bound and related integrins revealed opportunities increase potency selectivity, efforts were accelerated using accurate free energy perturbation (FEP+) calculations....
Abstract MM-111 is a novel bispecific antibody fusion protein which targets the ErbB2/ErbB3 oncogenic unit, blocking activation of phosphatidylinositol 3-kinase (PI3K) pro-survival pathway. The anti-ErbB2 arm binds with high affinity to ErbB2 receptor, localizes molecule over-expressing tumor cells and promotes binding anti-ErbB3 ErbB3 receptor. results in inhibition signaling by physiological ligand heregulin. treatment overexpressing cancer inhibits PI3K pathway sub-nanomolar potency,...
Abstract TNFR2 has been implicated as a novel target for cancer immunotherapy. While linked to enhanced suppressive activity of regulatory T cells (Tregs) in auto-immune models, the effect TNFR2-targeted therapy remains unclear. Here we present monoclonal anti-TNFR2 antibody that provides cell co-stimulation and yields robust anti-tumor vitro vivo models. In syngeneic murine tumor treatment with surrogate results both alone combination checkpoint inhibitor antibodies targeting PD-1 PDL-1....
Abstract #4166 ErbB3 has been identified as a preferred dimerization partner of ErbB2, critical for driving the proliferation ErbB2 over-expressing breast tumors. We have designed bispecific antibody, MM-111, which inhibits ligand-induced phosphorylation with sub-nanomolar potency by exploiting abundant expression its partner, specific targeting to cancer cells that express both receptors. employed computational physicochemical modeling guide kinetic optimization monovalent binding...
Abstract Introduction: Clinical studies in cancer patients have validated CD137 agonism as an activator of the immune system to enable tumor rejection. We demonstrated that small, chemically synthetic bicyclic peptides can drive tumor-localized and anti-tumor immunity mouse models. Here, we report next stage our work - delving into mechanism action these novel agents extending program serve whose tumors express EphA2. Experimental Procedures: MultiOmyx™ hyperplexed immunofluorescence assay...
Abstract Ephrins receptors are cell to adhesion molecules that mediate signaling and implicated in neuronal repulsion, migration angiogenesis. Ephrin receptor A2 (EphA2) is part of the ephrin family was shown be overexpressed several solid tumors including ovarian, gastric lung cancer associated with poor prognosis. MM-310 a novel EphA2 targeted docetaxel nanoliposome. Similar other nanoparticles, leverages organ specificity through enhanced permeability retention, but can also leverage...
Abstract HER2 is an important biomarker for breast and gastric cancer prognosis patient treatment decisions. positivity, as defined by IHC or FISH testing, remains imprecise predictor of response to HER2-targeted therapies. Challenges accurate assessment stratification may include intratumoral heterogeneity, lack assays that are quantitative and/or objective, differences between measuring at the protein vs. DNA level. We have developed a novel immunofluorescence method absolute quantitation...
Abstract TNFR2 is a member of the TNF receptor superfamily that upregulated upon T cell activation and highly expressed by tumor-infiltrating effector regulatory cells. We investigated levels on cells in syngeneic mouse tumor models secondary lymphoid tissues flow cytometry. Non-regulatory spleen lymph nodes little whereas Tregs constitutively intermediate levels. In contrast, high with expressing highest To investigate as therapeutic target, we generated novel monoclonal antibody specific...
Abstract Introduction. Ataxia telangiectasia and Rad3-related (ATR) protein kinases have been identified as a key part of the DNA damage repair processes (DDRP) cell cycle signaling. The DDRP is known to stimulate repair, promote survival and, consequently, can diminish therapeutic effect existing DNA-damaging chemotherapy agents ionizing radiation (IR) therapy. Therefore, there need for development potent selective therapies deliver ATR inhibitors treatment cancer, rational combination...
Abstract TNFR2, an emerging therapeutic target in immuno-oncology, is upregulated upon T cell activation and expressed by tumor-infiltrating effector regulatory (Treg) cells. We generated a novel monoclonal antibody, Y9, specific to murine TNFR2 investigated its mechanism of action. In vitro, Y9 stimulation purified cells increased proliferation function, indicating that acts as agonist can provide co-stimulation. vivo, treatment mice with established tumors resulted complete tumor clearance...
Abstract Ephrin receptor A2 (EphA2) is part of the family cell-cell junction proteins highly overexpressed in several solid tumors, and associated with poor prognosis. We developed a novel EphA2-targeted docetaxel nanoliposome, leveraging organ specificity through enhanced permeability effect cellular EphA2 targeting. The goal study was to develop diagnostic framework enabling clinical implementation EphA2-based exclusion criteria future MM-310 trials. used qFACS an vitro assay for liposome...