Sigalov A.B.,Signablok, Inc.
Molecular Immunology | Year: 2012
Cell surface receptors mediate many cellular responses in health and disease. Recent progress in our understanding of how ligand binding to the extracellular domains of receptors triggers intracellular signaling has underlined the role of ligand-promoted receptor clustering following by oligomerization of the cytoplasmic signaling domains. The clustering suggests the requirement of ligand multivalency and is especially important for triggering receptors involved in innate and adaptive immune responses. However, although numerous studies have established that multivalent, but not monovalent, ligands induce receptor-mediated signal transduction, considerable uncertainty still remains. Here, I hypothesize that " monovalent" ligands that have been reported to trigger immune receptors in vitro are not necessarily truly monovalent. This is illustrated by focusing on studies of signal transduction by toll-like receptor-4 and T cell receptor. By generalizing this concept to a variety of lipid and protein ligands, one would propose an alternative interpretation of apparent ligand monovalency in other receptor activation studies as well. © 2012 Elsevier Ltd. Source
Sigalov A.B.,Signablok, Inc.
Contrast Media and Molecular Imaging | Year: 2014
Magnetic resonance imaging (MRI) of macrophages in atherosclerosis requires the use of contrast-enhancing agents. Reconstituted lipoprotein particles that mimic native high-density lipoproteins (HDL) are a versatile delivery platform for Gd-based contrast agents (GBCA) but require targeting moieties to direct the particles to macrophages. In this study, a naturally occurring methionine oxidation in the major HDL protein, apolipoprotein (apo) A-I, was exploited as a novel way to target HDL to macrophages. We also tested if fully functional GBCA-HDL can be generated using synthetic apo A-I peptides. The fluorescence and MRI studies reveal that specific oxidation of apo A-I or its peptides increases the in vitro macrophage uptake of GBCA-HDL by 2-3 times. The in vivo imaging studies using an apo E-deficient mouse model of atherosclerosis and a 3.0T MRI system demonstrate that this modification significantly improves atherosclerotic plaque detection using GBCA-HDL. At 24h post-injection of 0.05mmol Gd kg-1 GBCA-HDL containing oxidized apo A-I or its peptides, the atherosclerotic wall/muscle normalized enhancement ratios were 90 and 120%, respectively, while those of GBCA-HDL containing their unmodified counterparts were 35 and 45%, respectively. Confocal fluorescence microscopy confirms the accumulation of GBCA-HDL containing oxidized apo A-I or its peptides in intraplaque macrophages. Together, the results of this study confirm the hypothesis that specific oxidation of apo A-I targets GBCA-HDL to macrophages in vitro and in vivo. Furthermore, our observation that synthetic peptides can functionally replace the native apo A-I protein in HDL further encourages the development of these contrast agents for macrophage imaging. © 2014 John Wiley & Sons, Ltd. Source
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 219.94K | Year: 2015
DESCRIPTION provided by applicant Carcinoma of the pancreas or pancreatic cancer PC is the fourth leading cause of cancer related death in the United States According to the American Cancer Society new cases and deaths are expected in Despite advances in therapy the year survival rate is less than Current treatments of PC include surgery radiation therapy chemotherapy and immunotherapy but they all only slightly prolong survival or relieve symptoms in patients with PC The limitations in efficacy of available treatments highlight the need for new treatments Pancreatic inflammation is known to increase the risk of PC High macrophage infiltration into the tumor mass correlates with the promotion of tumor growth and metastasis development As found recently triggering receptor expressed on myeloid cells TREM an inflammation amplifier plays a role in PC progression Expression of TREM on myeloid cells including tumor associated macrophages TAMs in patients with PC is upregulated and correlates to disease severity We hypothesize that TREM inhibition can improve survival of PC patients Current approaches to TREM suggest to block binding of ligand to TREM The true nature of the TREM ligand is not yet known highly increasing the risk of failure of these approaches in clinical development The long term objective of the proposed project is to develop a novel ligand independent approach to a TREM targeted treatment of PC The major goal of the Phase I study is to demonstrate that specific inactivation of TREM with novel inhibitory peptides suppresses PC tumor progression in animal model system and improves survival Phase I specific aims are to generate and characterize injectable formulations of TREM inhibitory peptides with different half lives and test the TREM inhibitory peptide formulations in a mouse model of PC The peptides will be designed using SignaBlokandapos s proprietary model of TREM signaling These non toxic peptides employ novel ligand independent mechanisms of action and are anticipated to have less severe side effects In order to increase peptide solubility bioavailability and targeting to TAMs we will utilize SignaBlokandapos s proprietary nanosystem for macrophage targeted delivery of water insoluble and poorly water soluble drugs We will use a BxPC xenograft mouse model of PC to test the ability of the peptides in free and particulate forms to inhibit cancer progression and promote survival It is anticipated that the proposed research will identify novel anticancer lead compounds that will set the stage for the development of new targeted therapies of PC thereby leading to a higher survival rate of the patients If successful the Phase I will be followed in te Phase II by toxicology absorption disposition metabolism excretion ADME pharmacology and chemistry manufacturing control CMC studies filing an Investigational New Drug IND application with the US Food and Drug Administration FDA and subsequent evaluation in humans Importantly TREM may play a role in the progression of not only PC but also other tumors Thus successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of tumors PUBLIC HEALTH RELEVANCE Pancreatic cancer is the fourth leading cause of cancer related death in the United States and the year survival rate is less than Current treatments are substantially ineffective and only slightly prolong survival or relieve symptoms in the cancer patients The proposed research is expected to result in the development of novel anticancer therapeutics that could substantially improve treatment of this type of cancer thereby leading to a higher survival rate of the patients
Signablok, Inc. | Date: 2010-10-10
A new approach to targeting imaging agents to macrophage-rich sites of interest is disclosed. Compositions of the invention are rHDL and HDL-like liposomal compositions, protein constituents of which, apolipoproteins A-I and/or A-II or fragments thereof are used not only as structural but also as targeting agents. This is achieved by certain controlled chemical or enzymatic modification of apolipoproteins A-I or A-II or fragments thereof. Such modification converts these apolipoproteins to substrates for macrophage scavenger receptors and results in the improvement of contrast agent-(HDL/modified apolipoprotein)-particle association with macrophages and/or absorption (uptake) by macrophages when compared to that of the contrast agent-(HDL/apolipoprotein)-particle constructed with non-modified naturally occurring apo A-I. The compositions can be used for noninvasive specific in vivo molecular detection and localization of macrophage-rich sites of interest using imaging techniques such as computed tomography (CT), gamma-scintigraphy, positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI).
Signablok, Inc. | Date: 2013-07-12
Peptides are provided consisting of L- and/or D-amino acids and combinations thereof, which affect myeloid cells by action on the triggering receptors expressed on myeloid cells (TREMs), including TREM-1 and TREM-2. The peptides act on the TREM/DAP-12 signaling complex. Also provided are lipid and sugar conjugated peptides comprising L- or D-amino acids. A method is provided of designing the peptides and lipid- and/or sugar-conjugated peptides comprising L- or D-amino acids. The disclosure relates to the therapy of various myeloid cell-related disease states involving the use of these peptides and compounds. The peptides and compounds are useful in the treatment and/or prevention of a disease or condition where myeloid cells are involved or recruited. The peptides of the present invention also are useful in the production of medical devices comprising peptide matrices (for example, medical implants and implantable devices).