Theranostics studies using 152/149Tb-labeled anti-CXCR4 probes in tumor mice

<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd">     <html xmlns="http://www.w3.org/1999/xhtml" lang="en" xml:lang="en" xmlns:og="http://ogp.me/ns#" xmlns:fb="http://ogp.me/ns/fb#"> <head> <title>Theranostics studies using 152/149Tb-labeled anti-CXCR4 probes in tumor mice - CERN Document Server</title> <link href='https://framework.web.cern.ch/framework/2.0/fonts/PTSansWeb/PTSansWeb.css' rel='stylesheet' type='text/css' /> <link rel="stylesheet" href="http://cds.cern.ch/img/invenio.css?v=20141127" type="text/css" /> <link rel="stylesheet" href="http://cds.cern.ch/img/cern_theme/css/cern_theme.css?v=20141127" type="text/css" /> <link rel="stylesheet"href="/css/font-awesome.min.css"> <meta http-equiv="X-UA-Compatible" content="IE=Edge"/> <link rel="stylesheet" href="http://cds.cern.ch/img/cern_toolbar/css/toolbar.css" type="text/css" />    <link rel="canonical" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic" /> <link rel="alternate" hreflang="el" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=el" /> <link rel="alternate" hreflang="fr" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=fr" /> <link rel="alternate" hreflang="bg" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=bg" /> <link rel="alternate" hreflang="zh-TW" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=zh_TW" /> <link rel="alternate" hreflang="pt" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=pt" /> <link rel="alternate" hreflang="no" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=no" /> <link rel="alternate" hreflang="hr" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=hr" /> <link rel="alternate" hreflang="ca" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=ca" /> <link rel="alternate" hreflang="de" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=de" /> <link rel="alternate" hreflang="it" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=it" /> <link rel="alternate" hreflang="zh-CN" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=zh_CN" /> <link rel="alternate" hreflang="sv" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=sv" /> <link rel="alternate" hreflang="sk" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=sk" /> <link rel="alternate" hreflang="en" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=en" /> <link rel="alternate" hreflang="pl" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=pl" /> <link rel="alternate" hreflang="ru" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=ru" /> <link rel="alternate" hreflang="ka" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=ka" /> <link rel="alternate" hreflang="ja" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=ja" /> <link rel="alternate" hreflang="es" href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic?ln=es" /> <link rel="alternate" type="application/rss+xml" title="CERN Document Server RSS" href="http://cds.cern.ch/rss" /> <link rel="search" type="application/opensearchdescription+xml" href="http://cds.cern.ch/opensearchdescription" title="CERN Document Server" /> <link rel="unapi-server" type="application/xml" title="unAPI" href="http://cds.cern.ch/unapi" /> <link rel="apple-touch-icon" href="/apple-touch-icon.png"/> <link rel="apple-touch-icon-precomposed" href="/apple-touch-icon-precomposed.png"/> <meta http-equiv="Content-Type" content="text/html; charset=utf-8" /> <meta http-equiv="Content-Language" content="en" /> <meta name="description" content="The chemokine receptor CXCR4 is a seven transmembrane G protein-coupled receptor and is involved in various inflammatory and autoimmune diseases, as well as in cancer metastasis and progression. Binding of the endogenous ligand CXCL12 (also known as stromal cell-derived factor-1α (SDF-1α)) to CXCR4 leads to activation of downstream signaling pathways that exert critical functions in development (organogenesis), normal physiology as well in disease processes. The central element in these processes is the migration of CXCR4-expressing cells towards tissues with high local SDF-1α expression, and their retention and differentiation at these sites. In cancer, the CXCR4-SDF-1α axis fulfils several tumor-growth supporting functions, including stimulation of tumor proliferation and angiogenesis, promotion of tumor invasiveness and moreover, it facilitates metastasis of CXCR4-expressing tumor cells to mesenchymal stromal tissues with high SDF-1α expression such as liver, bone marrow, lungs and lymph nodes.1 CXCR4 overexpression has been reported for multiple human tumor types, ranging from hematological malignancies (e.g. multiple myeloma) to solid tumors, including breast, prostate, lung and colorectal cancer. 3 Furthermore, CXCR4 expression is an important prognostic factor as high CXCR4 expression is correlated with distant metastasis and poor overall and disease-free survival in patients. Increased understanding of the pivotal role of CXCR4 in tumor biology has resulted in the development of positron emission tomography (PET) radiopharmaceuticals that can provide sensitive in vivo detection of CXCR4 expression and allow patient selection for CXCR4-targeted therapies. [68Ga]Pentixafor is the only CXCR4-targeted imaging agent that has found broad clinical applicability so far. Results with the therapeutic companion radiopharmaceutical [177Lu]pentixather are promising in treatment of multiple myeloma patients, but there is still room for improvement regarding efficacy, pharmacokinetics and dosimetry profile. TRNT causes substantially less collateral damage to normal tissues as compared to external radiotherapy. Due to the short path length and high linear energy transfer (LET) of α-particles, the DNA damage caused is much more difficult to repair than the DNA damage caused by β--particles. Furthermore, because of the limited range of the α-particle, radiotoxicity to the healthy surrounding cells is relatively low. An anti-CXCR4 radiopharmaceutical labeled with an α-emitter might present a breakthrough in therapy of various CXCR4-expressing tumors, especially before hematopoietic stem cell transplantation in lymphoproliferative or myeloid malignancies. The terbium (Tb) isotopes have been identified as a promising set of radioisotopes for performing both molecular imaging and targeted radiotherapy. Four Tb isotopes have been identified with nuclear properties that would be appropriate for different applications: 149Tb for targeted α-therapy; 152Tb for PET imaging; 155Tb for SPECT imaging; 161Tb for β- and Auger electron therapy.4,5 Especially the theranostic pair 152Tb (PET) and 149Tb (α) is very interesting for accurate dosimetry studies allowing targeted alpha therapy. We have identified at the laboratory for radiopharmaceutical research two promising new vector molecules to develop innovative CXCR4 radiopharmaceuticals, both for diagnostic and therapeutic purposes. The first vector molecule is a viral macrophage inflammatory protein-II (vMIP-II)-derived CXCR4 antagonist, composed entirely of D-amino acids (D-AA).10 We have derivatized the D-AA peptide with a suitable chelator, labeled the compound using the in-house developed Al18F-method and evaluated the pharmacokinetic properties of the new 18F-labeled anti-CXCR4 radiopharmaceutical in healthy and tumor mice using μPET/CT. The compound showed excellent pharmacokinetic properties with fast renal clearance and high and specific targeting of CXCR4 expressing tissues. Moreover, in vitro binding studies confirmed high affinity binding towards mouse and human CXCR4, showing the potential of this innovative vector molecule for the development of new diagnostic and therapeutic CXCR4-targeted radiopharmaceuticals. As second vector molecule, we have high affinity anti-CXCR4 nanobodies11 available with a C- terminal cysteine group, allowing site-specific radiolabeling methods. Nanobodies are heat-sensitive antigen-binding fragments derived from heavy chain-only antibodies occurring naturally in Camelid species. Nbs bind their antigens very fast and specifically with high affinity in vivo, whereas unbound Nbs are rapidly cleared from the blood by the kidneys. Physiological uptake of Nbs in liver and in abdomen is limited, therefore, Nbs can be considered as ideal vector molecules for in vivo imaging and targeted radionuclide therapy. First pilot experiments with 111In-labeled anti-CXCR4 nanobodies look promising and in vitro binding studies of natIn-DOTAGA-Nb confirmed the high affinity binding towards human CXCR4. In MED014 we have selected the most promising chelators for terbium in terms of radiolabeling properties and in vivo stability. Indeed, the research conducted in MED014 allows us to radiolabel heat-stable (e.g. D-AA peptide) and heat-sensitive (e.g. anti-CXCR4 nanobodies) vector molecules with a Tb radionuclide of interest in quantitative yields and high radiochemical purity. In this project we will radiolabel both vector molecules with 152Tb and evaluate the pharmacokinetics in hCXCR4- positive tumor mice using μPET/CT, combined with ex vivo biodistribution studies, radiometabolite studies and ex vivo autoradiography. Since the chemical structure and pharmacokinetics of the diagnostic and therapeutic anti-CXCR4 radioprobes are identical, the tracers can be used in a true “theranostic” approach. This will allow accurate dosimetry estimation. The most promising vector molecule will be used for toxicity and therapeutic efficacy studies with 149Tb-radioprobes in healthy mice and hCXCR4-positive tumor mice, respectively. Cleeren, Frederik" /> <meta name="keywords" content="MEDICIS, 149Tb, 152Tb, Terbium, Radioimmunotherapy, Chemokine receptor CXCR4, Nanobodies, Preclinical, Isotope mass separation" /> <script type="text/javascript" src="http://cds.cern.ch/js/jquery.min.js"></script>  <link rel="stylesheet" href="http://cds.cern.ch/img/webnews.css" type="text/css" />  <script type="text/javascript" src="http://cds.cern.ch/js/webnews.js?v=20131009"></script> <meta property="fb:app_id" content="137353533001720"/> <style></style> </head> <body class="search" lang="en">  <div id="cern-toolbar"> <h1><a href="http://cern.ch" title="CERN">CERN <span>Accelerating science</span></a></h1> <ul> <li class="cern-accountlinks"><a class="cern-account" href="https://cds.cern.ch/youraccount/login?ln=en&referer=http%3A//cds.cern.ch/record/2753398/files/MEDICIS-Theranostic" title="Sign in to your CERN account">Sign in</a></li> <li><a class="cern-directory" href="http://cern.ch/directory" title="Search CERN resources and browse the directory">Directory</a></li> </ul> </div>   <div role="banner" class="clearfix" id="header"> <div class="header-inner inner"> <hgroup class="clearfix"> <h2 id="site-name"> <a rel="home" title="Home" href="/"><span>CERN Document Server</span></a> </h2> <h3 id="site-slogan">Access articles, reports and multimedia content in HEP</h3> </hgroup> <div role="navigation" id="main-navigation" class="cdsmenu"> <h2 class="element-invisible">Main menu</h2><ul class="links inline clearfix"> <li class="menu-386 first active-trail"><a class="active-trail" href="http://cds.cern.ch/?ln=en">Search</a></li> <li class="menu-444 "><a class="" title="" href="http://cds.cern.ch/submit?ln=en">Submit</a></li> <li class="menu-426 "><a class="" href="http://cds.cern.ch/help/?ln=en">Help</a></li> <li class="leaf hassubcdsmenu"> <a hreflang="en" class="header" href="https://cds.cern.ch/youraccount/display?ln=en">Personalize</a> <ul class="subsubcdsmenu"><li><a href="https://cds.cern.ch/youralerts/list?ln=en">Your alerts</a></li><li><a href="https://cds.cern.ch/yourbaskets/display?ln=en">Your baskets</a></li><li><a href="https://cds.cern.ch/yourcomments?ln=en">Your comments</a></li><li><a href="https://cds.cern.ch/youralerts/display?ln=en">Your searches</a></li></ul></li> </ul> </div> </div> </div>  <table class="navtrailbox"> <tr> <td class="navtrailboxbody"> <a href="/?ln=en" class="navtrail">Home</a> > <a href="/collection/CERN%20Experiments?ln=en&as=0" class="navtrail">CERN Experiments</a> > <a href="/collection/MEDICIS%20Internal%20Notes?ln=en&as=0" class="navtrail">MEDICIS Internal Notes</a> > <a class="navtrail" href="http://cds.cern.ch/record/2753398">Theranostics studies using 152/149Tb-labeled anti-CXCR4 probes in tumor mice</a> > Access to Fulltext </td> </tr> </table> </div> <div class="pagebody"><div class="pagebodystripemiddle"> <div class="detailedrecordbox"> <div class="detailedrecordtabs"> <div> <ul class="detailedrecordtabs"><li class="first"><a href="http://cds.cern.ch/record/2753398/">Information </a></li><li class=""><a href="http://cds.cern.ch/record/2753398/references">References </a></li><li class=""><a href="http://cds.cern.ch/record/2753398/citations">Citations (0) </a></li><li class=""><a href="http://cds.cern.ch/record/2753398/keywords">Keywords </a></li><li class=""><a href="http://cds.cern.ch/record/2753398/comments">Discussion (0) </a></li><li class=""><a href="http://cds.cern.ch/record/2753398/usage">Usage statistics </a></li><li class="on"><a href="http://cds.cern.ch/record/2753398/files">Files </a></li><li class="disabled"><a>Plots </a></li><li class=""><a href="http://cds.cern.ch/record/2753398/holdings">Holdings </a></li><li class=""><a href="http://cds.cern.ch/record/2753398/linkbacks">Linkbacks </a></li></ul> <div id="tabsSpacer" style="clear:both;height:0px"> </div></div> </div> <div class="detailedrecordboxcontent"> <div class="top-left-folded"></div> <div class="top-right-folded"></div> <div class="inside">  <div id="detailedrecordshortreminder"> <div id="clip"> </div> <div id="HB"> <strong><a href="/record/2753398?ln=en">Theranostics studies using 152/149Tb-labeled anti-CXCR4 probes in tumor mice</a></strong> - <a href="/search?f=author&p=Cleeren%2C%20Frederik&ln=en">Cleeren, Frederik</a> - MED-031 </div> </div> <div style="clear:both;height:1px"> </div> <div style="width:90%;margin:auto;min-height:100px;margin-top:10px">  <small><b>main</b> file(s):</small><ul><table border="0" cellspacing="1" class="searchbox"> <tr><td colspan="2" class="restrictedfilerowheader">Restricted</td></tr> <tr> <td align="left" colspan="2" class="portalboxheader"> <img src='http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic%20studies%20using%20152%20149Tb-labeled%20anti-CXCR4%20probes%20in%20tumor%20mice.gif?subformat=icon' border="0" />  MEDICIS-Theranostic studies using 152 149Tb-labeled anti-CXCR4 probes in tumor mice </td> </tr><tr> <td class="portalboxheader"> <font size="-2">version 1</font> </td> <td> <table> <tr> <td valign="top"> <small><a href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic%20studies%20using%20152%20149Tb-labeled%20anti-CXCR4%20probes%20in%20tumor%20mice.gif?subformat=icon&version=1">MEDICIS-Theranostic studies using 152 149Tb-labeled anti-CXCR4 probes in tumor mice.gif (icon)</a></small> </td> <td valign="top"> <font size="-2" color="green">[2.28 KB]</font> <font size="-2"><em>01 Mar 2021, 19:21</em> </td> <td valign="top"><em></em></td> </tr><tr> <td valign="top"> <small><a href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic%20studies%20using%20152%20149Tb-labeled%20anti-CXCR4%20probes%20in%20tumor%20mice.jpg?subformat=icon-180&version=1">MEDICIS-Theranostic studies using 152 149Tb-labeled anti-CXCR4 probes in tumor mice.jpg (icon-180)</a></small> </td> <td valign="top"> <font size="-2" color="green">[3.01 KB]</font> <font size="-2"><em>01 Mar 2021, 19:21</em> </td> <td valign="top"><em></em></td> </tr><tr> <td valign="top"> <small><a href="http://cds.cern.ch/record/2753398/files/MEDICIS-Theranostic%20studies%20using%20152%20149Tb-labeled%20anti-CXCR4%20probes%20in%20tumor%20mice.pdf?version=1">MEDICIS-Theranostic studies using 152 149Tb-labeled anti-CXCR4 probes in tumor mice.pdf</a></small> </td> <td valign="top"> <font size="-2" color="green">[252.15 KB]</font> <font size="-2"><em>01 Mar 2021, 19:20</em> </td> <td valign="top"><em></em></td> </tr></table></td></tr></table></ul> </div> <div class="bottom-left-folded"></div> <div class="bottom-right-folded" style="text-align:right;padding-bottom:2px;"> <span class="moreinfo" style="margin-right:10px;"><a href="/search?ln=en&p=recid%3A2753398&rm=wrd" class="moreinfo">Similar records</a></span></div> </div> </div> </div> <br/> </div></div> <footer id="footer" class="pagefooter clearfix">  <div class="pagefooterstripeleft"> CERN Document Server :: <a class="footer" href="http://cds.cern.ch/?ln=en">Search</a> :: <a class="footer" href="http://cds.cern.ch/submit?ln=en">Submit</a> :: <a class="footer" href="https://cds.cern.ch/youraccount/display?ln=en">Personalize</a> :: <a class="footer" href="http://cds.cern.ch/help/?ln=en">Help</a> :: <a class="footer" href="https://cern.service-now.com/service-portal?id=privacy_policy&se=CDS-Service" target="_blank">Privacy Notice</a> <br /> Powered by <a class="footer" href="http://invenio-software.org/">Invenio</a> <br /> Maintained by <a class="footer" href="https://cern.service-now.com/service-portal?id=service_element&name=CDS-Service">CDS Service</a> - 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Theranostics studies using 152/149Tb-labeled anti-CXCR4 probes in tumor mice - CERN Document Server