Nanobody-mediated imaging and inhibition of the immune checkpoint ligand PD-L1

Quentin Lecocq
Mijn sciptie gaat over de nanobody gemedieerde beelvorming en blokkade van immuun checkpoint PD-L1. Het doel is om een middel te ontwikkelen die gebruikt kan worden voor zowel de diagnose en behandeling van kankerpatiënten.

Tumor omzeilt het immuunsysteem, het gebruik van nanobodies voor een gebalanceerde tegemoetkoming.

Tumor omzeilt het immuunsysteem, het gebruik van nanobodies voor een gebalanceerde tegemoetkoming.

Het idee om tumoren gevoeliger te maken voor een aanvallend immuunsysteem werd al klinisch toegepast m.b.v. antilichamen. Ondanks veelbelovende resultaten is er een noodzaak om ongewenste neveneffecten te vermeiden en de kost van de therapie te verlagen. Dit heeft geleid tot het ontdekken van een alternatief voor het gebruik van antilichamen. Een kameel afgeleide antigen-bindend fragment, vernoemd als een nanobody, heeft de voorbije jaren veel aandacht aangetrokken bij onderzoekers uit veel domeinen. Door hun stabiel en oplosbaar karakter, hoge affiniteit en specificiteit voor hun ligand en uitstekende weefsel penetratie zijn nanobodies bijzonder geschikt om in ons geval tumoren te targeten.

Theranostics, de brug slaan tussen diagnose en therapy.

Het immuunsysteem heeft het vermogen om specifiek tumor cellen te verwijderen gebaseerd op de uitdrukking van tumor antigenen. Tijdens dit proces wordt er ook een immunologisch geheugen gecreëerd om tumor herval te vermeiden. Dit fenomeen werd gestaafd door de observatie dat tumoren geïnfiltreerd worden met CD8+ cytotoxische immuuncellen, ook wel tumor infiltrerende lymfocyten genoemd. Recent ontwikkelde therapieën hebben als doel om een antitumor immuun respons op te wekken door de nodige stimuli te bezorgen om T-cellen te activeren in een antigen afhankelijke manier. Eens de actieve immuun cellen de tumor omgeving bereiken worden ze echter blootgesteld aan sterke inhibitorische signalen bezorgd door de tumor en hun ondersteunende cellen. Het blokkeren van deze signalen is een interessante methode om een immuun reactie tegen de tumorcellen te onderhouden en te versterken. Ook is het essentieel om kennis te hebben over welke inhibitorische signaal in de tumor omgeving van de patiënt een dominante rol speelt. Omdat er een lange lijst aan inhibitorische signalen bestaat is het belangrijk om de therapeutische aanpak af te stellen op de resultaten van de diagnose. Mijn scriptie « Nanobody-mediated imaging and inhibition of the immune checkpoint ligand PD-L1 » leert dat het gebruik van nanobodies, gericht tegen het inhibitorisch signaal PD-L1, veelbelovend is voor de diagnose en behandeling van kankerpatiënten.

PD-L1, een doordachte kandidaat uit een groeiende lijst van immuun checkpoints

PD-L1, of programmed death ligand 1, is een proteïne die onder andere aanwezig is op de celmembraan van bepaalde tumor cellen. De aanwezigheid van PD-L1 is deels verantwoordelijk voor het vermogen van een tumor om een gerichte aanval van het immuunsysteem plat te leggen. Dit komt doordat interactie van PD-L1 met onder andere de receptor PD-1, aanwezig op immuuncellen, een afremmend signaal sturen. Anderzijds zal deze interactie ook een signaal sturen naar de tumor die hen voorziet met een bescherming tegen geprogrammeerde celdood. Het is dus niet verwonderlijk dat de aanwezigheid van PD-L1 in verschillende types van tumoren gekoppeld wordt aan een slechte prognose [1].
[1]Muenst, S.; Schaerli, A. R.; Gao, F.; Daster, S.; Trella, E.; Droeser, R. A.; Muraro, M. G.; Zajac, P.; Zanetti, R.; Gillanders, W. E.; Weber, W. P.; Soysal, S. D., Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 2014, 146 (1), 15-

Het gebruik van nanobodies tegen PD-L1 als theranostic middel

In deze scriptie komen er twee toepassingen van nanobodies aan bod. Deze zijn (1) de visualisatie van PD-L1 op de membraan van cellen en (2) de therapeutische blokkade van PD-L1. Het idee om PD-L1 te visualiseren met behulp van nanobodies is ontstaan omdat er tot op de dag van vandaag geen accurate methode bestaat om de PD-L1 status op een tumor van een patiënt te analyseren. De methode is gebaseerd op de visualisatie van de opstapeling van PD-L1 gerichte nanobodies in PD-L1 rijke zones in het lichaam, bijvoorbeeld in een tumor. Men zou via deze techniek een dynamisch beeld over de PD-L1 op de tumor kunnen verkrijgen, die niet invasief en gevoeliger is dan de klassieke biopsie analyse die een statisch beeld weergeeft en altijd een operatie vereist. Ook zou men informatie kunnen verkrijgen over het al dan niet uitzaaien van de kanker.
Een tweede toepassing van nanobodies is het therapeutisch gebruik met oog op het versterken en ondersteunen van een tumor gerichte immuunreactie. PD-L1 bindende nanobodies zouden de interactie met onder andere PD-1 vermeiden, leidend tot een verhoogde activiteit van immuuncellen die de tumorcellen kunnen verwijderen.
In deze scriptie kan u meer informatie vinden omtrent de ontwikkeling en toekomstplannen van deze toepassingen.

Artikel Informatie:
Titel: Tumor omzeilt het immuunsysteem, het gebruik van nanobodies voor een gebalanceerde tegemoetkoming.
Auteur: Quentin Lecocq, master in de Biomedische wetenschappen (BMW)
Vrije Universiteit Brussel (VUB), Faculteit Geneeskunde en Farmacie, Laarbeeklaan 103, 1090 Jette
Masterproef: “Nanobody-mediated imaging and inhibition of the immune checkpoint ligand PD-L1”
Stageplaats: Laboratory for Molecular and Cellular Therapy (LMCT)
VUB, Faculteit Geneeskunde en Farmacie, Laarbeeklaan 103, Gebouw E – 1090 Jette
Jaar: 2015 - 2016
Indiendatum: 26 mei 2016

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Universiteit of Hogeschool
Biomedische wetenschappen
Publicatiejaar
2016
Promotor(en)
Professor Doctor Karine Breckpot
Kernwoorden
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