Publications by authors named "Manish Malviya"

11 Publications

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Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery.

Cancers (Basel) 2020 Aug 5;12(8). Epub 2020 Aug 5.

Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY 10065, USA.

The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics.
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http://dx.doi.org/10.3390/cancers12082175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465970PMC
August 2020

Treatment of experimental autoimmune encephalomyelitis with engineered bi-specific Foxp3+ regulatory CD4+ T cells.

J Autoimmun 2020 03 13;108:102401. Epub 2020 Jan 13.

Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paul Sabatier (UPS), Toulouse, France. Electronic address:

The use of autoantigen-specific regulatory T cells (Tregs) as a cellular therapy for autoimmune diseases is appealing. However, it is challenging to isolate and expand large quantity of Tregs expressing disease-relevant T-cell receptors (TCR). To overcome this problem, we used an approach aiming at redirecting the specificity of polyclonal Tregs through autoreactive TCR gene transfer technology. In this study, we examined whether Tregs engineered through retroviral transduction to express a TCR cross-reactive to two CNS autoantigens, myelin oligodendrocyte glycoprotein (MOG) and neurofilament-medium (NF-M), had a superior protective efficacy compared with Tregs expressing a MOG mono-specific TCR. We observed that engineered Tregs (engTregs) exhibited in vitro regulatory effects related to the antigenic specificity of the introduced TCR, and commensurate in potency with the avidity of the transduced TCR. In experimental autoimmune encephalomyelitis (EAE), adoptively transferred engTregs proliferated, and migrated to the CNS, while retaining FoxP3 expression. EngTregs expressing MOG/NF-M cross-reactive TCR had superior protective properties over engTregs expressing MOG-specific TCR in MOG-induced EAE. Remarkably, MOG/NF-M bi-specific TCR-engTregs also improved recovery from EAE induced by an unrelated CNS autoantigen, proteolipid protein (PLP). This study underlines the benefit of using TCRs cross-reacting towards multiple autoantigens, compared with mono-reactive TCR, for the generation of engTregs affording protection from autoimmune disease in adoptive cell therapy.
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http://dx.doi.org/10.1016/j.jaut.2020.102401DOI Listing
March 2020

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody.

Ann Clin Transl Neurol 2017 11 3;4(11):768-783. Epub 2017 Oct 3.

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany.

Objective: Autoimmune encephalitis is most frequently associated with anti-NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form.

Methods: Patients with recent onset typical anti-NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy- (IgH) and light-chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.

Results: Intrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen-driven intrathecal immune response. Consistently, a single recombinant human GluN1-specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.

Interpretation: A CNS-specific humoral immune response is present in anti-NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti-NMDAR encephalitis as a humorally mediated autoimmune disease.
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http://dx.doi.org/10.1002/acn3.444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682115PMC
November 2017

Dose-dependent inhibition of demyelination and microglia activation by IVIG.

Ann Clin Transl Neurol 2016 11 23;3(11):828-843. Epub 2016 Sep 23.

Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf Moorenstr. 5 D-40225 Duesseldorf Germany.

Objective: Intravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Clinical trials of IVIG for multiple sclerosis, using diverse dose regimens, yielded controversial results. The aim of this study is to dissect IVIG effector mechanisms on demyelination in an model of the central nervous system (CNS)-immune interface.

Methods: Using organotypic cerebellar slice cultures (OSC) from transgenic mice expressing green fluorescent protein (GFP) in oligodendrocytes/myelin, we induced extensive immune-mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective IVIG effects were assessed by live imaging of GFP expression, confocal microscopy, immunohistochemistry, gene expression analysis and flow cytometry.

Results: IVIG protected OSC from demyelination in a dose-dependent manner, which was at least partly attributed to interference with complement-mediated oligodendroglia damage, while binding of the anti-MOG antibody was not prevented. Staining with anti-CD68 antibodies and flow cytometry confirmed that IVIG prevented microglia activation and oligodendrocyte death, respectively. Equimolar IVIG-derived Fab fragments or monoclonal IgG did not protect OSC, while Fc fragments derived from a polyclonal mixture of human IgG were at least as potent as intact IVIG.

Interpretation: Both intact IVIG and Fc fragments exert a dose-dependent protective effect on antibody-mediated CNS demyelination and microglia activation by interfering with the complement cascade and, presumably, interacting with local immune cells. Although this experimental model lacks blood-brain barrier and peripheral immune components, our findings warrant further studies on optimal dose finding and alternative modes of application to enhance local IVIG concentrations at the site of tissue damage.
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http://dx.doi.org/10.1002/acn3.326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099529PMC
November 2016

Endotracheal intubation in a neonatal population remains associated with a high risk of adverse events.

Eur J Pediatr 2011 Feb 15;170(2):223-7. Epub 2010 Sep 15.

Neonatal intensive Care Unit, Rosie Hospital, Cambridge, UK.

Introduction: There has been a significant increase in premedication use for neonatal intubation in the UK over the past decade. We aimed to determine the adverse events during neonatal intubation using the most commonly used premedication regimen in the UK.

Discussion: We prospectively studied all intubations performed using morphine, suxamethonium and atropine during a 3-month period in three UK tertiary neonatal units. Premedication was administered for 87/93 (94%) of intubations. Median time taken to prepare premedication was 16 min (IQR 10-35). Median time to successful intubation was 5 min (IQR 2-9) following premedication. Median lowest recorded oxygen saturation after administration of premedication was 65% (IQR 39-85). A bradycardia in the range 61-99/min accompanied the procedure in 24/93 (26%) intubations, with a median duration of bradycardia of 8 s (IQR 1-10).

Conclusion: Despite the widespread move to premedication for neonatal intubation, many deficiencies in everyday practice remain. The rate of haemodynamic complications is high in this commonly used premedication regimen. This study shows that there are important factors to control at the local level in terms of timely preparation and administration of premedication drugs, training and supervision of staff carrying out this high-risk procedure.
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http://dx.doi.org/10.1007/s00431-010-1290-8DOI Listing
February 2011

Muscarinic receptor 1 agonist activity of novel N-aryl carboxamide substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models.

Bioorg Med Chem 2009 Aug 21;17(15):5526-34. Epub 2009 Jun 21.

Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, Karnataka, India.

Earlier we have reported the effect of arecoline thiazolidinone and morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer's presenile dementia models. To elucidate further our Structure-Activity Relationship (SAR) studies on the chemistry and muscarinic receptor 1 binding efficacy, a series of novel carboxamide derivatives of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine molecule have been designed and synthesized as a new class of M1 receptor agonists with a low toxicity effect profile that enhances memory function in animal models of Alzheimer's presenile dementia and also modulates the APP secretion from rat brain cerebrocortical slices by activating M1 receptor in vitro. Results suggest that compound 9b having methyl group at the para position of the aryl group attached to the carboxamide of morpholino arecoline could emerge as a potent molecule having antidementia activity.
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http://dx.doi.org/10.1016/j.bmc.2009.06.032DOI Listing
August 2009

Active site directed docking studies: synthesis and pharmacological evaluation of cis-2,6-dimethyl piperidine sulfonamides as inhibitors of acetylcholinesterase.

Eur J Med Chem 2009 Oct 8;44(10):4057-62. Epub 2009 May 8.

Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore - 570006, Karnataka, India.

Hypocholinergic function associated with Alzheimer's disease (AD) is well-accepted hypothesis, in this regard, many research attempts have been made to elevate the reduced cholinergic neurotransmission, among them two main treatment strategies were widely explored, namely stimulation of muscarinic receptor 1 and/or reversible inhibition of acetylcholinesterase (AChE) enzyme. In an attempt to improve the efficacy and to minimize general side effects of these AChE inhibitors, many lead molecules are developed in research; one among them is piperidine derivative. Donazepil is a widely prescribed AChE inhibitor which displays a piperidine ring in its structure. In the present study, we have docked cis-2,6-dimethyl piperidine sulfonamides (3a-i) on AChE enzyme and synthesized by nucleophilic substitution reaction between cis-2,6-dimethyl piperidine and alkyl/aryl sulfonyl chlorides in the presence of triethylamine. These piperidine sulfonamides were subjected to in vitro AChE enzyme inhibition studies and in vivo antiamnesic study to reverse scopolamine induced memory loss in rats. Two derivatives (3a and f) in this class of piperidines (3a-i) showed considerable inhibition against different sources of AChE in vitro and reduced average number of mistakes done by wistar rats as compared to scopolamine treated group in vivo (rodent memory evaluation).
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http://dx.doi.org/10.1016/j.ejmech.2009.04.042DOI Listing
October 2009

Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models.

Bioorg Med Chem 2008 Aug 2;16(15):7095-101. Epub 2008 Jul 2.

Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.

As part of our continuing effort aimed at the development of selective, efficacious and centrally active M1 muscarinic agonists for the treatment of Alzheimer's presenile dementia, a series of N-arylthioureas substituted 3-morpholino arecoline derivatives 9(a-j) were synthesized by using N-benzyl amino ethanol coupling with alpha-bromo acetyl pyridine followed by reduction and cyclization to develop a new class of M1 receptor agonists. Subsequently the synthesized compounds were subjected to in vitro radioligand M1 receptor affinity studies, IP3 formation studies and also to in vivo pharmacological evaluation of memory and learning in male Wistar rats. Derivatives with chloro (9f) and methoxy (9c) groups on the para position of the benzene ring attached to the nitrogen of thiourea showed several fold high affinity for the M1 receptor (in vitro) among all the synthesized molecules 9(a-j), and also significantly elevated IP3 levels and as well elicited beneficial effects in vivo in memory and learning models in rats (rodent memory evaluation, plus and Y maze studies).
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http://dx.doi.org/10.1016/j.bmc.2008.06.053DOI Listing
August 2008

In vivo effect of antidepressants on [3H]paroxetine binding to serotonin transporters in rat brain.

Neurochem Res 2008 Nov 25;33(11):2250-6. Epub 2008 Apr 25.

Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560 029, India.

Amine transporters are major target for development of various pharmacological agents to treat behavioral disorders. Serotonin transporters (SERT) have been implicated in the etiology of depression and drugs acting on SERT can be effective in treating depression. The aim of the present study was to study the in vivo effect of various antidepressants on [(3)H]paroxetine binding to SERT in regions of rat brain. Rats were treated with tricyclic antidepressant (TCAs) such as amitriptyline (AMI), serotonin/norepinephrine reuptake inhibitor (SNRIs) such as clomipramine (CMI), and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) and citalopram (CIT) (10 mg/kg body wt.) for 30 days. Density of SERT was measured in cortex and hippocampus using [(3)H]paroxetine (0.03-1.0 nM) in presence and absence of 10 muM fluoxetine as displacer. It was observed that the density of cortical SERT was significantly decreased with CMI (68%, P < 0.0001), FLX (67%, P < 0.0001), CIT (54%, P < 0.0001), and AMI (52%, P < 0.0001) treatment, when compared to the density of 120.7 +/- 4.0 fmol/mg protein in control rats, without altering the affinity (Kd) of [(3)H]paroxetine to the transporters. The density of SERT in hippocampus was also significantly decreased with FLX (65%, P < 0.0001), CMI (54%, P < 0.0001), CIT (52%, P < 0.0001) and AMI (46%, P < 0.0001) treatment, when compared to the density of 74.0 +/- 2.6 fmol/mg protein in control rats, without altering the affinity of [(3)H]paroxetine to the transporters. Displacement study showed high affinity for CMI > CIT > FLX. The results suggest that chronic antidepressant treatment significantly down-regulates both cortical and hippocampal SERT in rat brain and SSRIs have high affinity for SERT than TCAs.
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http://dx.doi.org/10.1007/s11064-008-9703-zDOI Listing
November 2008

Effect of novel N-aryl sulfonamide substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer's dementia models.

Bioorg Med Chem 2008 May 8;16(9):5157-63. Epub 2008 Mar 8.

Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.

A series of novel, potent, and selective muscarinic receptor 1 agonists (M1 receptor agonists) that employ a key N-substituted morpholine Arecoline moiety has been synthesized as part of research effort for the therapy of Alzheimer's diseases. The ester group of arecoline (which is reported as muscarinic agonist) has been replaced by N-substituted morpholine ring. The structure-activity relationship reveals that the electron donating 4-substituted sulfonyl derivatives (9a, 9b, 9c, and 9e) on the nitrogen atom of the morpholine ring increases the affinity of M1 receptor binding 50- to 80-fold greater than the corresponding arecoline. Other derivatives also showed considerable M1 receptor binding affinity.
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http://dx.doi.org/10.1016/j.bmc.2008.03.019DOI Listing
May 2008

Effect of novel arecoline thiazolidinones as muscarinic receptor 1 agonist in Alzheimer's dementia models.

Neurochem Int 2008 Feb 10;52(3):376-83. Epub 2007 Jul 10.

Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.

The discovery of cholinergic deficit in Alzheimer's disease (AD) patient's brain has triggered research efforts, using cholinomimetic approaches for their efficacy in AD therapy. Various therapies may be of potential clinical use in AD. Among these are cholinergic agents, which include muscarinic agonists, acetylcholinesterase inhibitors, and acetylcholine releasing agents. One of the muscarinic agonists tested in AD is arecoline and its bioisosters, which are widely explored as muscarinic receptor 1 agonist (M1 receptor agonist) in AD research. In this regard, five-membered heterocyclic ring system attached arecoline basic nucleus (N-methyl tetrahydropyridines) at third position has been extensively researched on. The present research involved synthesis of arecoline thiazolidinones 5(a-j) by using dipolar addition of 3-aminopyridine and alkyl/aryl carboxaldehydes in presence of gamma ferrite as catalyst. The resulting products were methylated and reduced to get desired products. Subsequently the synthesized arecoline thiazolidinones were subjected to in vitro muscarinic receptor binding studies using male Wistar rat brain (cerebral cortex) membrane homogenate and extended this in vitro study to in vivo pharmacological evaluation of memory and learning in male Wistar rats. Four derivatives (5a-5c and 5e) showed considerable M1 receptor binding affinity (in vitro) and elicited beneficial effects in vivo memory and learning models (Rodent memory evaluation, plus and Y maze studies).
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http://dx.doi.org/10.1016/j.neuint.2007.07.006DOI Listing
February 2008
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