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Development of More Precise and Efficient Antibodies for Cancer Targeting: Membrane Associated Form Specific Anti- Mesothelin Antibodies and CAR As an Example

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Development of More Precise and Efficient Antibodies for Cancer Targeting: Membrane Associated Form Specific Anti- Mesothelin Antibodies and CAR As an Example Development of more precise and efficient antibodies for cancer targeting : membrane associated form specific anti-mesothelin antibodies and CAR as an example Kamal Asgarov To cite this version: Kamal Asgarov. Development of more precise and efficient antibodies for cancer targeting :mem- brane associated form specific anti-mesothelin antibodies and CAR as an example. Immunotherapy. Université de Franche-Comté, 2016. English. NNT : 2016BESA3013. tel-01617531 HAL Id: tel-01617531 https://tel.archives-ouvertes.fr/tel-01617531 Submitted on 16 Oct 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE DE FRANCHE-COMTE UFR SCIENCES MEDICALES ET PHARMACEUTIQUES DE BESANCON ECOLE DOCTORALE « ENVIRONNEMENT, SANTE » Année Universitaire 2015-2016 THESE Pour l’obtention du Diplôme de Doctorat de l’Université de Franche-Comté Spécialité : Sciences de la Vie et de la Santé Development of more precise and efficient antibodies for cancer targeting: Membrane associated form specific anti- mesothelin antibodies and CAR as an example. Soutenue le 13 décembre 2016 par ASGAROV Kamal Sous la direction du Pr Christophe BORG et Dr Bernard ROYER Membres du Jury : Directeur de thèse : Docteur Bernard ROYER Co-directeur de thèse : Professeur Christophe BORG Rapporteurs : Professeur Mohamed Hebbar Professeur Jan de Mey Examinateurs : Professeur Robin FAHREUS Docteur Andy CLARK Docteur John Wijdenes Remerciements Tout d’abord je remercie toute l’équipe de l’UMR 1098, particulièrement Professeur Philippe Saas, Professeur Olivier Adotevi, Docteur Yann Godet, Docteur Christophe Ferrand, tous les étudiants et tout le personnel de m’avoir accueilli et soutenu pendant toutes ces années. Je tiens à remercier les membres du jury qui m’ont fait l’honneur d’accepter de juger mon travail. Merci en particulier au Professeur Robin Fahreus pour avoir fait le déplacement ainsi qu’au Professeur Mohamed Hebbar et au Docteur Jan de Mey qui ont accepté de lire et d’évaluer la qualité de ce travail effectué lors de cette thèse. Je tiens à remercier également le Professeur Christophe Borg, qui m’a accueilli au sein de son équipe dès mon Master 2. Je le remercie pour la confiance qu’il m’a accordé, son soutien indéfectible et son enthousiasme. J’ai beaucoup appris à vos côtés, et grâce à vous j’ai beaucoup évolué personnellement et approfondi mes connaissances scientifiques. Je souhaite remercier tout particulièrement le Docteur Bernard Royer pour ces précieux conseils et sa bonne humeur à toute épreuve. Merci à John Wijdenes et Andy Clark pour leur soutien particulier pour le projet, et de m’avoir fait confiance pour développer cette technique de production d’anticorps au sein de la plateforme ITAC (Innovative Target Against Cancer). Merci tout particulièrement à John pour ces conseils scientifiques précieux. Merci à Docteur Clark d’avoir pris de son temps pour mon article. Je n’oublie pas non plus mon ex-camarade Afag Asgarova qui a gradé avant moi. Merci à toi aussi pour ton soutien et ton amitié et ton aide pour l’intégration au sein de l’équipe. Merci à l’ensemble de mes collègues de la Plateforme ITAC qui m’ont intégré, et permis de travailler avec plaisir et qui m’ont témoigné jusqu’au bout leurs encouragements. Merci à Jérémy pour son aide et ses conseils sur la technique du Phage Display mais surtout pour son amitié et ses blagues originales toujours là où on ne les attend pas. Merci à Charline 1 et Adeline pour leurs précieuses aides sur les techniques de cytométrie et de culture cellulaires qui m’ont permis de finaliser et aboutir à cette thèse. Merci particulièrement à Charline pour ces manips de « compétitions » et Adeline pour toutes les immunisations qu’elle a réalisé et les Immuno-précipitations qu’elle m’a promis. Merci à Tic et Tac pour leur présence joyeuse, leur soutien à fond et leur gentillesse. Je remercie également mes collègues, Virginie, Vincent, Patricia, Jean Paul, J-R, Lise, Jeanne, Laurent, Walid, Emilie, Marie, Elise, Laurie et Sindy pour leur soutien et leur gentillesse. A mes amis, en particulier Ilkin pour son soutien moral ; et Hakan pour ses petits plats et ses discussions toujours appréciées. Je souhaite remercier du fond du cœur toute ma famille qui m’a toujours encouragé. En particulier ma Maman qui m’a toujours soutenu et encouragé mais qui est partie trop tôt pour voir l’aboutissement de ce travail. Merci à mon Papa, ma sœur, et mon frère qui, malgré l’éloignement, m’ont toujours soutenu. Une petite pensée pour mon grand-père et ma grand- mère qui aurait été fier de me voir me hisser au sommet de mon doctorat. Merci aussi à Fatima qui a toujours été présente et surtout qui a gérer les enfants et m’a laissé du temps pour l’écriture de ce manuscrit. Merci à elle pour son soutien sans faille même dans les moments difficiles. Et merci à mes deux enfants, Nilufer et Atilla pour le bonheur et le courage qu’ils m’ont apporté à travers chaque éclat de rire. Merci à Docteur Stefano Kim et à son épouse Guadalupe Tizon pour leur assistance sur la rédaction en anglais. 2 Contents REMERCIEMENTS ............................................................................................................................................. 1 ABREVIATIONS ................................................................................................................................................. 8 LIST OF FIGURES ............................................................................................................................................. 14 LIST OF TABLE ................................................................................................................................................. 16 ABSTRACT ...................................................................................................................................................... 17 INTRODUCTION .............................................................................................................................................. 19 CANCER AND IMMUNOTHERAPY ................................................................................................................... 21 I. FDA APPROVED MONOCLONAL ANTIBODIES FOR CANCER TREATMENT .................................................................... 22 a. Structure .................................................................................................................................................. 23 b. Antibody engineering approaches ........................................................................................................... 26 1. Hybridoma technology .................................................................................................................................... 26 2. Phage display ................................................................................................................................................... 28 c. Mechanism of action ................................................................................................................................ 36 1. ADCC and CDC ...................................................................................................................................................... 37 d. Pharmacokinetics of antibodies ............................................................................................................... 41 e. Targets for therapeutic antibodies .......................................................................................................... 43 1. Cell differentiation (CD) antigens: .................................................................................................................. 43 2. Growth factors:..................................................................................................................................................... 45 3. Immune-checkpoint molecules ............................................................................................................................ 48 f. Antibody-drug conjugates ........................................................................................................................ 54 II. CAR T CELL CLINICAL TRIALS ........................................................................................................................... 56 a. Introduction........................................................................................................................................ 56 b. Functionality and acting mechanism ................................................................................................. 57 3 c. Different generations ......................................................................................................................... 59 d. Clinical trials ....................................................................................................................................... 61 III MESOTHELIN AS A TARGET FOR CANCER THERAPY ....................................................................................................
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