GENERATION AND VALIDATION OF NANOBODIES TARGETING BRAIN TUMORS WITH ABERRANT EXPRESSION OF EPIDERMAL GROWTH FACTOR RECEPTOR AND HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2

Heleen Hanssens Janik Puttemans Serge Muyldermans
onderzoek naar het vermogen van kleine antilichaamfragmenten om hersentumoren te bereiken

Hersentumoren genezen met kamelenbloed?

Hersentumoren. We zijn ze liever kwijt dan rijk. Maar toch is het één van de  meest voorkomende kankers bij kinderen jonger dan 15 jaar. Behandeling van dit soort tumoren is moeilijk en meestal is een volledige genezing niet mogelijk. Dat maakt dat de diagnose van een hersentumor nog steeds een quasi doodsvonnis is anno 2018.

Er bestaan twee soorten hersentumoren: primaire hersentumoren, die ontstaan uit gezonde hersencellen, en secundaire hersentumoren, die uitzaaiingen zijn van andere kankersoorten, zoals de belangrijke borstkankers. De behandeling van beide soorten bestaat uit een keuze uit of combinatie van chirurgie, bestraling en chemotherapie waarbij kankerbestrijdende middelen worden toegediend. De laatste decennia wordt er veel onderzoek gedaan naar deze specifieke geneesmiddelen, en ook naar methodes om kankercellen te onderscheiden van gezonde cellen.

Als ons lichaam in contact komt met een indringer, zoals een bacterie of virus, treedt ons natuurlijk afweermechanisme, het immuunsysteem, in werking en worden er antilichamen geproduceerd: moleculen die in staat zijn om de indringers te herkennen en te elimineren. Kankercellen zijn in wezen ook indringers, maar omdat ze zo sterk gelijken op gezonde cellen, worden ze door ons immuunsysteem niet herkend als lichaamsvreemd en dus ook met rust gelaten. In laboratoria heeft men nu technieken ontwikkeld om toch antilichamen aan te maken, die specifiek kankercellen kunnen herkennen en binden, en die via het bloed aan de patiënt kunnen worden toegediend. Dit is het basisprincipe van de immuuntherapie, een techniek die bij verschillende kankers zijn nut en efficiëntie al heeft bewezen. 

Bij hersentumoren ligt dit moeilijker en slaat deze techniek niet aan, en daar is reden voor: de bloedhersenbarrière. Dat is een soort microfilter die onze hersenen beschermt voor mogelijk schadelijke stoffen of indringers. Gewone antilichamen zijn grote moleculen die zeer moeilijk door deze filter geraken. Anderzijds heeft onderzoek uitgewezen dat de filter in geval van een tumor soms niet meer goed werkt en antilichamen de tumor toch zouden kunnen vinden. In dat geval echter, zorgt het gezond hersenweefsel ervoor zorgt dat die antilichamen niet meer goed werken. Pech dus. Of toch niet?

25 jaar geleden werd er aan de Vrije Universiteit Brussel een toevallige en bijzondere ontdekking gedaan in het bloed van kameelachtigen. Deze dieren maken naast de gewone antilichamen ook een speciale soort antilichamen aan: de zware-ketenantilichamen. Deze zijn kleiner dan de gewone antilichamen, die bestaan uit zware én lichte ketens, en hebben bovendien een ander herkenningsgedeelte. Dit deeltje wordt ook nanobody genoemd, en kan gebruikt worden als een aparte molecule om indringers te herkennen en te binden. Een nanobody is ongeveer tien keer kleiner dan een gewoon antilichaam en onderzoek heeft al verschillende voordelen kunnen aantonen ten opzichte van deze laatste. Zo zijn ze sneller in het vinden en bereiken van indringers in het lichaam, en ze worden ook sneller uit het lichaam verwijderd via de urine.

Het doel in deze masterthesis was het onderzoeken naar de capaciteiten van nanobodies om hersentumoren te bereiken, en om na te gaan of ze er meer geschikt voor zouden zijn dan de standaard antilichamen. Mijn onderzoek heeft zich voornamelijk gericht op hersenmetastasen van een veelvoorkomende borstkanker, in een testsetting met muizen. Zowel antilichamen als nanobodies werden gemerkt met een radioactieve stof. De radioactieve straling kunnen we meten wat ons toelaat om te berekenen hoeveel nanobody in de tumor geraakt.

Met dit onderzoek hebben we kunnen aantonen dat zowel antilichamen als nanobodies in staat zijn om de hersentumor te bereiken. Echter wel met wezenlijke verschillen. Antilichamen kunnen veel meer radioactieve straling in de tumor brengen. Maar omwille van hun grootte bewegen ze zich veel trager doorheen het lichaam en bereiken ze de tumor veel later. Nanobodies daarentegen zijn veel vinniger: ze zijn al voldoende meetbaar in de tumor na een uur, terwijl dit voor de antilichamen drie à vier dagen duurt om een maximum dosis te bereiken. Dit opent perspectieven naar de behandeling van deze tumoren. Men kan aan het nanobody een therapeutisch type radioactiviteit koppelen, zodat het de kankercel waaraan het zich hecht kan bestralen en schade toebrengen. Doet met dit met antilichamen, dan zal er ook schade aangericht worden aan gezonde weefsels, waar het antilichaam “treuzelt” omwille van zijn grootte en bijhorende traagheid. Er is echter een maar. De kleine vinnige nanobodies passeren ook vlot de nierfilter en worden dus ook snel via de urine uitgescheiden, hetgeen nierschade zou kunnen veroorzaken bij gebruik van radioactiviteit. Momenteel wordt er dan ook veel onderzoek gedaan naar een manier om de nierschade te verminderen om op die manier een ideaal type molecule te ontwikkelen voor de gerichte radiotherapie van tumoren in de hersenen.

Een andere belangrijke moeilijkheid in de behandeling van hersentumoren is de chirurgische verwijdering. Het is namelijk uitermate moeilijk om gezond hersenweefsel te onderscheiden van kankercellen in het brein. En aangezien hersenen zo delicaat en complex zijn, kunnen dokters niet zomaar meer weefsel wegnemen om zeker te zijn dat de hele tumor is verwijderd. Nanobodies kunnen ook hier een oplossing bieden. Door er een soort fluorescerende stof aan te binden, kan men de slechte cellen laten oplichten, zodat hersentumoroperaties veel preciezer kunnen gebeuren.

Samengevat hebben we in deze masterthesis een aantal veelbelovende mogelijkheden van nanobodies in het domein van de neuro-oncologie aangetoond, zowel op het vlak van meer gerichte radiotherapie, als op het vlak van beeldgeleide operaties. Deze toevallig ontdekte kleine moleculen uit kamelenbloed zouden daarom wel eens een grote stap kunnen betekenen in de behandeling van hersentumoren, een domein waarin de vraag naar meer efficiënte therapieën enorm is.

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Universiteit of Hogeschool
Master of Science in Bio Engineering Sciences – Cell and Gene Biotechnology
Publicatiejaar
2018
Promotor(en)
Nick Devoogdt
Kernwoorden
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