A5077228616- Immune Cell Function and Interaction
- Reproductive System and Pregnancy
- Adenosine and Purinergic Signaling
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Virus-based gene therapy research
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Adolescent and Pediatric Healthcare
- Viral Infectious Diseases and Gene Expression in Insects
- RNA Interference and Gene Delivery
- CRISPR and Genetic Engineering
- Macrophage Migration Inhibitory Factor
- Nanoplatforms for cancer theranostics
- Peptidase Inhibition and Analysis
- Epigenetics and DNA Methylation
- Pneumocystis jirovecii pneumonia detection and treatment
- Autoimmune Bullous Skin Diseases
- Quinazolinone synthesis and applications
- Cancer Mechanisms and Therapy
- Immune cells in cancer
- Melanoma and MAPK Pathways
- Click Chemistry and Applications
- Bipolar Disorder and Treatment
- Platelet Disorders and Treatments
Regeneron (United States)
2024
Amgen (United States)
2012-2017
Stanford University
2008-2012
Institute of Structural and Molecular Biology
2010
Cornell University
2002
Abstract Interactions between HLA-C ligands and inhibitory killer cell Ig-like receptors (KIR) control the development response of human NK cells. This regulatory mechanism is usually described by mutually exclusive interactions KIR2DL1 with C2 having lysine 80, KIR2DL2/3 C1 asparagine 80. Consistent this simple rule, we found from functional analysis binding assays to 93 HLA-A, HLA-B, isoforms that KIR2DL1*003 bound all C2, only allotypes. The allotypically related KIR2DL2*001 KIR2DL3*001...
We explored the mechanism of action CD39 antibodies that inhibit ectoenzyme conversion extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinflammatory responses. Using syngeneic humanized tumor models, we contrast potency anti-CD39 mAbs with other agents targeting adenosinergic pathway. demonstrate critical importance an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway in antitumor activity mediated by enzyme blockade, rather than simply reducing adenosine as...
Human killer cell immunoglobulin-like receptors (KIRs) are distinguished by expansion of activating KIR2DS, whose ligands and functions remain poorly understood. The oldest, most prevalent KIR2DS is KIR2DS4, which represented a variable balance between “full-length” “deleted” forms. We find that full-length 2DS4 human histocompatibility leukocyte antigen (HLA) class I receptor binds specifically to subsets C1+ C2+ HLA-C HLA-A*11, whereas deleted nonfunctional. Activation 2DS4+ NKL cells was...
Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using murine version virus, we characterized local and systemic antitumor immune responses driving efficacy in syngeneic models.Experimental Design: The activity talimogene laherparepvec was against melanoma cell lines using an vitro viability assay. Efficacy OncoVEXmGM-CSF (talimogene with mouse granulocyte-macrophage colony-stimulating factor transgene) alone or...
Natural killer (NK) cells contribute to the essential functions of innate immunity and reproduction. Various genes encode NK cell receptors that recognize major histocompatibility complex (MHC) Class I molecules expressed by other cells. For primate cells, killer-cell immunoglobulin-like (KIR) are a variable rapidly evolving family MHC receptors. Studied here is KIR3DL1/S1, which encodes for highly polymorphic human HLA-A -B comprises three ancient allelic lineages have been preserved...
Natural killer (NK) cells contribute to immunity and reproduction. Guiding these functions, NK cell education, are Ig-like receptors (KIR), that recognize HLA class I. In most human populations, highly polymorphic ligands combine with extraordinary diversity. To assess how much of this diversity is necessary, we studied KIR I at high resolution in the Yucpa, a small South Amerindian population survived an approximate 15,000-year history bottleneck epidemic infection, including recent viral...
Interactions between killer immunoglobulin-like receptors (KIRs) and their HLA-A, -B, -C ligands diversify the functions of human natural cells. Consequently, combinations KIR HLA genotypes affect resistance to infection autoimmunity, success reproduction outcome hematopoietic cell transplantation. HLA-C, with its C1 C2 epitopes, evolved in hominids be specialized ligands. The system's foundation was epitope, a later addition, by several million years. inhibitory receptor for is encoded...
Abstract Through recognition of HLA class I, killer cell Ig-like receptors (KIR) modulate NK functions in human immunity and reproduction. Although a minority HLA-A -B allotypes are KIR ligands, HLA-C dominate this regulation, because they all carry either the C1 epitope recognized by KIR2DL2/3 or C2 KIR2DL1. The C1-specific evolved first, followed several million years later C2-specific KIR. Strong, varying selection pressure on drove diversification divergence hominid KIR, with six...
Natural killer (NK) cell protection from tumor metastases is a critical feature of the host immune response to cancer, but various immunosuppression mechanisms limit NK effector function. The ectoenzyme, CD39, expressed on tumor-infiltrating myeloid cells, granulocytes, and lymphocytes, including converts extracellular ATP (eATP) into AMP and, thus, potentially suppresses eATP-mediated proinflammatory responses. A CD39-targeting monoclonal antibody (mAb) that inhibits mouse ectoenzyme CD39...
Natural killer (NK) cells serve essential functions in immunity and reproduction. Diversifying these within individuals populations are rapidly-evolving interactions between highly polymorphic major histocompatibility complex (MHC) class I ligands variable NK cell receptors. Specific to simian primates is the family of Killer Immunoglobulin-like Receptors (KIR), which recognize MHC associate with a range human diseases. Because KIR have considerable species-specificity lacking from common...
Abstract Modulation of human NK cell function by killer Ig-like receptors (KIR) and MHC class I is dominated the bipartite interactions inhibitory lineage III KIR with C1 C2 epitopes HLA-C. In comparison, ligand specificities functional contributions activating remain poorly understood. Using a robust, sensitive assay binding representative panel 95 HLA targets, we show that KIR2DS1 binds ~50% avidity KIR2DL1, whereas KIR2DS2, KIR2DS3, KIR2DS5 have no detectable for C1, C2, or any other...
Interactions between HLA class I and killer cell Ig-like receptors (KIRs) diversify human NK responses. Dominant KIR ligands are the C1 C2 epitopes of MHC-C, a young locus restricted to humans great apes. C1- C1-specific KIRs evolved first, being present in orangutan functionally like their counterparts. Orangutans lack C2-specific KIRs, but have unique C1+C2-specific that binds equally C2. A receptor with this specificity likely provided mechanism by which C2-KIR interaction from C1-KIR...
Ly49 lectin-like receptors and killer cell Ig-like (KIR) are structurally unrelated surface glycoproteins that evolved independently to function as diverse NK for MHC class I molecules. Comparison of primates various domesticated animals has shown species have either a or KIR gene family, but not both. In four pinniped wild marine carnivore, three seals one sea lion, we find each represented by single, orthologous genes exhibit little polymorphism transcribed express protein. Pinnipeds...
Abstract Humans and chimpanzees have orthologous MHC class I, but few killer cell Ig-like receptors (KIR). Most divergent are lineage III KIR, which in humans include the inhibitory KIR2DL1 2DL2/3 specific for HLA-C. Six chimpanzee KIR were identified as candidate MHC-C studied using cytolytic assays, to assess capacity of a defined function with I allotype, direct binding assays KIR-Fc fusion proteins. Pt-KIR2DL6 2DL8 demonstrated be C1 specificity specificity-determining residue (lysine...
Meeting abstracts Talimogene laherparepvec (T-VEC) is an injectable modified oncolytic herpes simplex virus type-1 (HSV-1) hypothesized to be efficacious by at least two complimentary mechanisms of action: a) direct oncolysis the injected tumor and b) elicitation a systemic anti-tumor immune
Abstract Background: The ecto-ATPase CD39 is the rate-limiting enzyme in adenosine pathway that plays an important immune regulatory role. Preclinically, inhibition of by TTX-030, a first-in-class fully human anti-CD39 antibody, reversed immunosuppression maintaining high levels immune-stimulatory extracellular ATP while reducing suppressive adenosine. addition nivolumab to chemotherapy has recently become standard care 1st-line (1L) treatment locally advanced or metastatic (LA/M) gastric...
Abstract The ATP/Adenosine pathway in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. ATPase CD39 is highly expressed TME, both on infiltrating immune cells and across a broad set of cancer indications. processes pro-inflammatory extracellular ATP to ADP AMP, which then processed by CD73, immunosuppressive adenosine. Inhibiting enzymatic function potential shift milieu TME 2-pronged fashion: 1) Enhancement immunostimulatory released damaged and/or...
Meeting abstracts Talimogene laherparepvec, an investigational oncolytic immunotherapy, is a modified herpes simplex virus type-1 (HSV-1) designed to selectively replicate in tumors and initiate systemic immune response target cancer cells. Intralesional administration of talimogene
<h3>Background</h3> Circulating tumor DNA (ctDNA) holds promise as an early endpoint in oncology drug development, particularly advanced non-small cell lung cancer (aNSCLC) treated with immunotherapy. Friends of Cancer Research established the ctMoniTR Project to aggregate and analyze patient-level data from clinical trials generate evidence that characterizes association between change ctDNA levels on-treatment associations overall survival (OS). Using well characterized 4 randomized...
<h3>Background</h3> Human leukocyte antigen-G (HLA-G) is an immune checkpoint molecule that belongs to the non-classical HLA-class I family of receptors. HLA-G restrains cell activation and effector function by engaging with inhibitory receptors ILT2 ILT4. While expression highly restricted under normal healthy conditions, we have demonstrated its in cancer aberrantly upregulated broadly detected across a variety tumor types. Tizona Therapeutics has generated novel, fully human antibody...