A5007306710- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Synthesis and Biological Evaluation
- Radiopharmaceutical Chemistry and Applications
- Cancer Cells and Metastasis
- Chemical Synthesis and Analysis
- interferon and immune responses
- Cancer Genomics and Diagnostics
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- CAR-T cell therapy research
- RNA modifications and cancer
- Peptidase Inhibition and Analysis
- RNA Research and Splicing
- Computational Drug Discovery Methods
- Epigenetics and DNA Methylation
- Neuroblastoma Research and Treatments
- Nuclear Structure and Function
- Microtubule and mitosis dynamics
- Estrogen and related hormone effects
- Innovative Microfluidic and Catalytic Techniques Innovation
- Virus-based gene therapy research
- Biotin and Related Studies
- Genomics and Chromatin Dynamics
- Cancer Treatment and Pharmacology
Mersana Therapeutics (United States)
2018-2024
Pfizer (United States)
2011-2018
The University of Texas MD Anderson Cancer Center
2011
Pfizer (United Kingdom)
2011
Columbia University
2005-2007
Harvard University
1999-2002
Dana-Farber Cancer Institute
1999-2002
Comparative genomics of CpG dinucleotides, which are targets DNA methyltransferases in vertebrate genomes, has been constrained by their evolutionary instability and the effect methylation on mutation rates. We compared human chimpanzee genomes to identify sequence signatures correlated with rates at dinucleotides. The new were used develop robust comparative dinucleotides heterogeneous regions genomic domains that have anomalous divergence data showed there approximately 200 where...
PTK7 is a tumor-initiating cell antigen, which can be targeted with an antibody-drug conjugate to confer sustained tumor regressions.
Abstract Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate tumor cell-directed agonist antibody-drug-conjugates (STINGa ADCs) activate in cells myeloid induce anti-tumor innate immune vitro, vivo (in female mice), ex models. We show the STINGa ADCs are internalized into by Fcγ-receptor-I antigen-dependent...
Triple-negative breast cancer (TNBC) and ovarian each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel that target eradicate tumor-initiating cells (TIC) are needed to significantly improve survival.A panel of well-annotated patient-derived xenografts (PDX) was established, surface markers enriched TIC in specific tumor subtypes were empirically determined. The TICs queried overexpressed antigens, one selected be the an antibody-drug conjugate...
Abstract Antibody–drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop novel ADC that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells (TIC), which comprise most aggressive cell population in tumor. optimized anti-5T4 (A1mcMMAF) by sulfydryl-based conjugation humanized A1 antibody tubulin inhibitor monomethylauristatin F (MMAF) via maleimidocaproyl linker. A1mcMMAF exhibited potent vivo antitumor...
Tumorigenesis depends on intricate interactions between genetically altered tumor cells and their surrounding microenvironment. While oncogenic drivers in lung squamous carcinoma (LUSC) have been described, the role of stroma modulating tissue architecture, particularly cell polarity, remains unclear. Here, we report establishment a 3D coculture system LUSC epithelial with cancer-associated fibroblasts (CAFs) extracellular matrix that together capture key components microenvironment (TME)....
While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results yet translated in the clinic. A agonist antibody–drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration well tumor-localized activation of greater activity and better tolerability. In line with this effort, a ADC platform was identified through systematic optimization payload, linker, scaffold based on multiple...
Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many types. The activity safety profile of an ADC depends on its construction: antibody, payload, linker, conjugation method, as well the number payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for optimization given target antigen, we developed Dolasynthen (DS), novel platform based auristatin hydroxypropylamide, that enables precise DAR-ranging site-specific...
Proteins to be transported into the nucleus are recognized by members of importin-karyopherin nuclear transport receptor family. After docking at pore complex (NPC), cargo-receptor moves through aqueous channel. Once cargo is released, importin then back channel for new rounds transport. Thus, and exportin, another member this family involved in export, thought continuously shuttle between interior cytoplasm. In order understand how transporters traverse NPC, we constructed functional...
Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and time to recurrence following treatment. Here, we integrate multiple experimental models clinicopathologic analysis of delineate a cellular hierarchy NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells worse clinical outcome Coexpression factors involved epithelial-to-mesenchymal transition were observed undifferentiated but not tumor...
Abstract Purpose: Targeted tumor delivery may be required to potentiate the clinical benefit of innate immune modulators. The objective study was apply an antibody-drug conjugate approach STING agonism and develop a candidate. Methods: XMT-2056, HER2-directed STING-agonist (ADC), designed, built, tested in pharmacology toxicology studies. ADC compared benchmark intravenously administered agonist. Results: XMT-2056 achieved tumor-targeted agonist upon systemic administration mice induced...
DNA methyltransferase 1 (DNMT1) has been reported to interact with a wide variety of factors and contain intrinsic transcriptional repressor activity. When conservative point mutation was introduced at the key catalytic residue, mutant DNMT1 failed rescue any phenotypes Dnmt1-null embryonic stem (ES) cells, which indicated that biological functions are exerted through methylation DNA. ES cells expressed protein did not survive differentiation. Intracisternal A-particle family...
Abstract We present here a novel therapeutic agent, XMT-2056, that results in robust anti-tumor activity mediated by an immune response through targeted delivery of STING agonist to the tumor microenvironment. By leveraging antibody-drug conjugate (ADC) strategy, systemic administration with tumor-targeted can be achieved, potentially overcoming limitations either intratumoral or intravenous administrations unconjugated, small molecule agonists. XMT-2056 was generated conjugation...
Abstract STING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an innate anti-tumor immune response. While in principle systemic administration of agonist would have many benefits, including the delivery all tumor lesions, such approach may be limited by toxicity. Antibody-drug conjugates (ADCs) constitute proven modality that is ideally suited enable without associated toxicity concerns via targeted strategy. Herein, we demonstrate systemically administered...
Abstract STING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an innate anti-tumor immune response. However, the systemic administration of free agonist may be limited by toxicity, and broad biodistribution not ideal. Antibody-drug conjugates (ADCs) constitute proven modality that enables tumor-targeted delivery thus is ideally suited with reduced toxicity. To develop optimized STING-agonist ADC platform, we designed novel specifically tailored for use in ADC....
Abstract XMT-2056 is a systemically administered Immunosynthen STING agonist antibody-drug conjugate (ADC) that targets novel HER2 epitope and induces complete tumor regressions with single dose in multiple models. We have previously shown delivers its payload into cells FcγRI (CD64)-expressing myeloid cells, activating signaling both cell types, leading to type I interferon (IFN) anti-tumor innate immune responses. Here, we demonstrate exhibits ADCC (antibody-dependent cell-mediated...