Design, synthesis, and assessment of specific iNKT cell agonists for clinical applications
Lead Research Organisation:
University of Birmingham
Department Name: Sch of Biosciences
Abstract
The proposed research will address fundamental questions about the influence of the structural activity relationship of CD1d-restricted iNKT cells and how we may take advantage of both their immunostimulatory and immunoregulatory properties to help treat a number of clinical conditions. By using an informed design approach to generating new iNKT cell agonists, we hope to develop a more rational strategy to exploit the diverse immunomodulatory properties of this family of compounds as potential immunotherapeutic drugs. iNKT?ncell?nligands such as alpha-GalCer associated analogues, and other novel synthetic agonists, have potential use in three therapeutic areas. First, the Th1 cytokine-inducing properties of alpha-GalCer-based agents could provide protection against a variety of pathogens as a short-term immunostimulatory boost. Second, the non-specific immune activation properties of these compounds may be exploited as vaccine immunoadjuvants to boost cytotoxic responses to various neoplasias and infectious diseases, and third, the Th2 cytokine-inducing properties of iNKT cell agonists may prove effective at controlling auto-aggressive immune responses. The key challenge remains how to activate and manipulate the different functions of iNKT cells selectively, through the use of specific agonists, which can then be translated into clinical applications. As the complex structures of current iNKT agonists based on alpha-GalCer are not particularly suitable for clinical development, there is an urgent need to develop new simpler compounds that are capable of inducing targeted human iNKT cell responses. This will be achieved by a process of informed, structural design. In addition we intend to maximise our chances of success by making structural modifications to the parent iNKT cell agonist, alpha-GalCer, to create new analogues, based on our previously acquired knowledge of the structural activity relationships (SAR!
s) that influence/govern their biological outcome. We will also use more sophisticated human in vitro screening assays to improve clinical translation of new agonists. In this application, our philosophy is to deliver a multidisciplinary, state-of-the-art programme of studies in order to address these goals. The proposed methodologies are novel and include: chemical synthesis, in silico design, human in vitro screening assays and novel in vivo verification models.
s) that influence/govern their biological outcome. We will also use more sophisticated human in vitro screening assays to improve clinical translation of new agonists. In this application, our philosophy is to deliver a multidisciplinary, state-of-the-art programme of studies in order to address these goals. The proposed methodologies are novel and include: chemical synthesis, in silico design, human in vitro screening assays and novel in vivo verification models.
Technical Summary
Invariant natural killer T cells (iNKT cells) are one of the key sentinel cells of the innate immune system. Their activation by foreign lipid antigens, dictates and directs a subsequent adaptive immune response to this stimulus, and in this way, microbial activation of iNKT cells can result in dendritic and B cell maturation, promoting specific cellular and antibody responses against invading pathogens. iNKT cells are also important mediators of cancer immunosurveillance, acting via direct recognition and lysis of malignant cells or through subsequent Th1 cytokine release, which promotes NK cell anti-tumour activity. These properties indicate their potential clinical application in developing both anti-microbial and anti-tumour vaccination/treatment strategies. In contrast to these immune-system-activating properties, iNKT cells also play a major role in suppressing autoimmune responses via induction of inhibitory Th2 cytokines and/or promotion of regulatory T cells to self-lipid antigens. In this mode of operation, they have the potential to suppress autoimmune diseases, such as NOD, EAE, and SLE. Whilst iNKT cells exhibit wide-ranging responses to activation, the key challenge remains how to activate and manipulate the different potential functions of iNKT cells selectively, through the use of specific agonists, which can then be translated into clinical applications. We believe this is now possible through a greater understanding of the structure-activity relationships (SARs) that govern iNKT-TCR-CD1d interactions, which can direct the design of new agonists towards predictable biological outcomes. By studying the SARs of previously identified glycolipid agonists, we have already identified a number of parameters including: i) binding affinity, ii) direct presentation or requirement for internalisation and processing, and iii) co-stimulatory molecule recruitment and activation, that dictate the type of immune response that results upon iNKT cell activation. We now propose to generate new iNKT cell agonists with simplified architectures and tailored immunological responses, which can be applied for therapeutic use. Assessment of their clinical potential will also be enhanced by the incorporation of various novel human in vitro assays into our bioactivity screening programme.
Publications
Wojno J
(2012)
Amide analogues of CD1d agonists modulate iNKT-cell-mediated cytokine production.
in ACS chemical biology
Fox LM
(2013)
Expression of CD1c enhances human invariant NKT cell activation by a-GalCer.
in Cancer immunity
Jervis PJ
(2012)
Towards multivalent CD1d ligands: synthesis and biological activity of homodimeric a-galactosyl ceramide analogues.
in Carbohydrate research
Arora P
(2016)
"Endocytic pH regulates cell surface localization of glycolipid antigen loaded CD1d complexes"
in Chemistry and Physics of Lipids
O'Konek JJ
(2013)
ß-mannosylceramide activates type I natural killer t cells to induce tumor immunity without inducing long-term functional anergy.
in Clinical cancer research : an official journal of the American Association for Cancer Research
Dossa RG
(2015)
In contrast to other species, a-Galactosylceramide (a-GalCer) is not an immunostimulatory NKT cell agonist in horses.
in Developmental and comparative immunology
Jimeno R
(2019)
Tissue-specific shaping of the TCR repertoire and antigen specificity of iNKT cells.
in eLife
Saez De Guinoa J
(2017)
CD1d-mediated activation of group 3 innate lymphoid cells drives IL-22 production.
in EMBO reports
Kerscher B
(2016)
Mycobacterial receptor, Clec4d (CLECSF8, MCL), is coregulated with Mincle and upregulated on mouse myeloid cells following microbial challenge.
in European journal of immunology
Volarevic V
(2015)
Gal-3 regulates the capacity of dendritic cells to promote NKT-cell-induced liver injury.
in European journal of immunology
Melo AM
(2019)
Mucosal-Associated Invariant T Cells Display Diminished Effector Capacity in Oesophageal Adenocarcinoma.
in Frontiers in immunology
Nguyen TK
(2013)
The bovine CD1D gene has an unusual gene structure and is expressed but cannot present a-galactosylceramide with a C26 fatty acid.
in International immunology
Cameron G
(2015)
Antigen Specificity of Type I NKT Cells Is Governed by TCR ß-Chain Diversity.
in Journal of immunology (Baltimore, Md. : 1950)
Shenderov K
(2013)
Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome.
in Journal of immunology (Baltimore, Md. : 1950)
Wen X
(2015)
A Subset of CD8aß+ Invariant NKT Cells in a Humanized Mouse Model.
in Journal of immunology (Baltimore, Md. : 1950)
O'Brien A
(2019)
Obesity Reduces mTORC1 Activity in Mucosal-Associated Invariant T Cells, Driving Defective Metabolic and Functional Responses.
in Journal of immunology (Baltimore, Md. : 1950)
Birkholz AM
(2015)
A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-? Production.
in Journal of immunology (Baltimore, Md. : 1950)
Bénézech C
(2015)
Inflammation-induced formation of fat-associated lymphoid clusters.
in Nature immunology
Wu L
(2012)
Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice.
in Proceedings of the National Academy of Sciences of the United States of America
Brennan PJ
(2014)
Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction.
in Proceedings of the National Academy of Sciences of the United States of America
Van Rhijn I
(2016)
Human autoreactive T cells recognize CD1b and phospholipids.
in Proceedings of the National Academy of Sciences of the United States of America
Salio M
(2013)
Saposins modulate human invariant Natural Killer T cells self-reactivity and facilitate lipid exchange with CD1d molecules during antigen presentation.
in Proceedings of the National Academy of Sciences of the United States of America
León L
(2012)
Saposins utilize two strategies for lipid transfer and CD1 antigen presentation.
in Proceedings of the National Academy of Sciences of the United States of America
Vomhof-DeKrey EE
(2015)
Cognate interaction with iNKT cells expands IL-10-producing B regulatory cells.
in Proceedings of the National Academy of Sciences of the United States of America
Tatituri RV
(2013)
Recognition of microbial and mammalian phospholipid antigens by NKT cells with diverse TCRs.
in Proceedings of the National Academy of Sciences of the United States of America
Paduraru C
(2013)
Role for lysosomal phospholipase A2 in iNKT cell-mediated CD1d recognition.
in Proceedings of the National Academy of Sciences of the United States of America
Bedard M
(2019)
Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells.
in Proceedings of the National Academy of Sciences of the United States of America
Kunte A
(2013)
Endoplasmic reticulum glycoprotein quality control regulates CD1d assembly and CD1d-mediated antigen presentation.
in The Journal of biological chemistry
Pellicci DG
(2014)
The molecular bases of d/aß T cell-mediated antigen recognition.
in The Journal of experimental medicine
| Title | galactosyl ceramide derivatives |
| Description | New derivatives of galactosyl ceramide to promote Th1 responses, and cross-talk between NKT and B cells |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Initial development |
| Year Development Stage Completed | 2009 |
| Development Status | Actively seeking support |
| Impact | None |