Abstract
Adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD+) are released as danger signals from cells during infection and sterile inflammation. In the extracellular compartment ATP is converted by CD39, CD73, and other ecto-enzymes into metabolites that modulate the activity of T cells and macrophages. While ATP mediates pro-inflammatory signals via P2X7 and other P2 receptors, adenosine triggers anti-inflammatory signaling via the adenosine 2a receptor (Adora2a) and other P1 receptors. The latter also plays a role in maintaining an immunosuppressive tumor microenvironment. NAD+ is converted by CD38, CD203 and other ecto-enzymes to the Ca2+ mobilizing messengers cyclic ADP-ribose and ADP-ribose, and to adenosine. Recent findings on the roles of CD38, CD39, CD73, CD203, P2X7, and Adora2a in inflammation and immunity underscore the potential of these proteins as drug targets. However, available small molecule inhibitors often lack specificity and mediate unwanted off-target toxicity. Nanobodies – single domain antibodies derived from heavy chain antibodies that naturally occur in camelids – display a propensity to bind functional epitopes not accessible to conventional antibodies. Like conventional antibodies, nanobodies and nanobody-based biologics are highly specific and have well-understood, tunable in vivo pharmacodynamics with little if any toxicity. Nanobodies thus represent attractive alternatives to small molecule inhibitors for modulating purinergic signaling in inflammation and immunity. Here we review recent progress made in developing nanobodies against key targets of purinergic signaling.
Highlights
Purinergic signaling by extracellular Adenosine triphosphate (ATP), NAD+ and their metabolites is recognized as an important regulatory mechanism in inflammation and immunity (Junger, 2011; Eltzschig et al, 2012; Idzko et al, 2014; Burnstock, 2016)
In the extracellular compartment ATP is converted by CD39, CD73, CD203 and related enzymes into adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine, metabolites that modulate the activity of T cells and macrophages
NAD+ is converted by CD38, CD73, and CD203 into nicotinamide and the Ca2+ mobilizing messengers cyclic ADP-ribose and ADP-ribose (ADPR), and to adenosine (Figure 1C)
Summary
Purinergic signaling by extracellular ATP, NAD+ and their metabolites is recognized as an important regulatory mechanism in inflammation and immunity (Junger, 2011; Eltzschig et al, 2012; Idzko et al, 2014; Burnstock, 2016). The effective functional blockade of ARTC2.2 enzyme activity by the injected nanobodies and nanobody-based heavy chain antibodies could readily be monitored on T cells recovered from lymphatic tissues of nanobody-injected mice: both formats effectively blocked ARTC2.2-catalyzed ADP-ribosylation of cell surface proteins and ARTC2.2-mediated NICD (Koch-Nolte et al, 2007; Hubert et al, 2010; Scheuplein et al, 2010). ATP, NAD+ and their metabolites act as ligands for ionotropic (P2X) and metabotropic (P1, P2Y) receptors, many of which are expressed by immune cells (Burnstock and Boeynaems, 2014; Di Virgilio and Vuerich, 2015) Targeting these cell surface receptors with antagonistic and/or agonistic nanobodies might provide novel therapeutic approaches in inflammation and immunity.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
