Antibody-based pharmacodelivery of immunomodulators for the treatment of ulcerative colitis
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1 Research Collection Doctoral Thesis Antibody-based pharmacodelivery of immunomodulators for the treatment of ulcerative colitis Author(s): Bootz, Franziska S. Publication Date: 2016 Permanent Link: Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library
2 DISS. ETH NO ANTIBODY-BASED PHARMACODELIVERY OF IMMUNOMODULATORS FOR THE TREATMENT OF ULCERATIVE COLITIS A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich) presented by FRANZISKA SOPHIE BOOTZ Master of Science ETH Zürich in Medicinal and Industrial Pharmaceutical Sciences born on citizen of Germany accepted on the recommendation of Prof. Dr. Dario Neri (examiner) Prof. Dr. Roger Schibli (co-examiner) 2016
3 1 Abstract The majority of medicinal products do not selectively accumulate at the site of disease, which may lead to side effects. One strategy to avoid this off-target toxicity and to increase selectivity consists in the use of antibodies as vehicles to selectively deliver drugs to sites of disease, while sparing healthy tissues. The antibody-based pharmacodelivery of therapeutic agents has been extensively studied for various indications but not for the treatment of inflammatory bowel diseases. In this thesis, we report that the alternativelyspliced EDA domain of fibronectin, a marker of angiogenesis and tissue remodelling, is expressed in the dextran sodium sulphate mouse model of colitis and in patients with inflammatory bowel conditions, while being virtually undetectable in most healthy adult tissues. Radiolabeled preparations of the F8 antibody, specific to the EDA domain of fibronectin, were shown to selectively localize to sites of inflammation in mice with colitis, as revealed by autoradiographic analysis showing a 23-fold stronger signal in the inflamed colon compared to the healthy control. Fusion proteins comprising the F8 antibody and various murine cytokine payloads with potential disease-ameliorating activity were generated. Candidates exhibiting favourable biochemical properties and suitable tissue distribution profiles were then tested in the DSS-induced mouse model of colitis in a therapeutic setting. In a first therapy experiment, fusion proteins of the F8 antibody with interleukin- 4, the p40-subunit of interleukin-12 or interleukin-13 were administered to mice with colitis. F8-IL12p40 mediated an anti-inflammatory activity, which was comparable to the one of cyclosporine, while F8-IL4 did not inhibit colitis and F8-IL13 worsened the inflammatory condition. Despite its beneficial effect in DSS-induced colitis, F8-IL12p40 exhibited a poor tissue distribution profile with little tumor uptake (1.16 ± 0.44 %ID/g) and low tumor to organ ratios. The impact of glycosylation on unfavourable in vivo performance was investigated using enzymatically and genetically generated 1
4 glycosylation variants of F8-IL12p40. The enzymatically deglycosylated protein revealed a slightly improved biodistribution profile (2.2 ± 0.6 %ID/g tumor uptake), whereas genetically engineered mutants lacking either one or three out of four potential glycosylation sites exhibited a tissue distribution similar to the one of the parental protein. In the last part of this thesis, we describe the cloning and therapeutic properties of novel antibody-based fusion proteins, comprising the F8 antibody and murine interleukin-22, a globular cytokine belonging to the interleukin-10 family. Both F8-IL22 and IL22-F8 were able to selectively accumulate at the site of disease. The fusion protein with the cytokine moiety at the N-terminal extremity (IL22-F8) exhibited better results than the C-terminal fusion, both in terms of targeting selectivity and therapeutic efficacy. Mice treated with IL22-F8 showed a more rapid recovery from clinical symptoms compared to controls, as well as improved macroscopic and microscopic morphology of the colon. 2
5 2 Zusammenfassung Die Mehrzahl medizinischer Produkte reichert sich nicht selektiv am Krankheitsherd an was zu Nebenwirkungen im gesunden Gewebe führen kann. Eine Herangehensweise, diese unerwünschten Toxizität in nicht erkranktem Gewebe zu vermeiden und die Selektivität zu erhöhen, ist die Verwendung von Antikörpern als Trägermoleküle um Arzneimittel selektiv zum Krankheitsherd zu transportieren und somit gesundes Gewebe zu schonen. Die zielgerichtete Anreicherung von Wirkstoffen mit Hilfe von Antikörper- Trägermolekülen wurde zwar in verschiedenen Indikationsgebieten ausgiebig untersucht, allerdings nicht bei Chronisch-entzündlichen Darmerkrankungen. In dieser Arbeit beschreiben wir die Expression der alternativ gespleißten EDA Domäne von Fibronektin, einem Marker für Angiogenese, in einem Mausmodel der Natrium-Dextransulfat induzierten Kolitis und in Patienten mit entzündlichen Erkrankungen des Darms. In gesundem Gewebe ist dieses Protein nahezu nicht nachweisbar. Eine autoradiografische Analyse in Mäusen mit experimenteller Kolitis zeigte eine entzündungsspezifische Anreicherung radioaktiv markierter Proteinpräparate des Antikörpers F8, welcher spezifisch an EDA bindet. Im Vergleich zu gesundem Gewebe konnte im Entzündungsherd eine 23-fach erhöhte Signalintensität nachgewiesen werden. Fusionsproteine bestehend aus dem F8 Antikörper und verschiedenen murinen Zytokinen mit potenzieller krankheitslindernder Wirkung wurden erzeugt. Produkte, die vorteilhafte biochemische Eigenschaften und geeignete Biodistributionsprofile aufwiesen wurden daraufhin im Mausmodell der Natrium- Dextransulfat induzierten Kolitis auf ihren therapeutischen Nutzen hin getestet. In einem ersten Therapie-Experiment wurden Fusionsproteine des F8 Antikörpers mit Interleukin-4, Interleukin 13 oder der p40 Untereinheit von Interleukin-12 an Mäuse mit Kolitis verabreicht. F8-IL12p40 vermittelte eine mit Ciclosporin vergleichbare entzündungshemmende Wirkung, wohingegen F8-IL4 die Kolitis nicht linderte und F8-IL13 den entzündlichen Zustand sogar verschlimmerte. Trotz der genesungsfördernden Wirkung wies F8-IL12p40 ein mangelhaftes Biodistributionsprofil auf, welches eine geringe Aufnahme im Tumor (1.16 ±
6 %ID/g) und ein niedriges Verteilungsverhältnis vom Tumor zu den restlichen Organen beinhaltete. Die Auswirkungen des Glykosylierungsmuster auf das ungünstige in vivo Verhalten wurde mit Hilfe von enzymatisch und genetisch hergestellten Glykosylierungsvarianten untersucht. Das enzymatisch deglykosylierte Protein zeigte ein leicht verbessertes Biodistributionsprofil (2.2 ± 0.6 %ID/g Tumoraufnahme) während die gentechnisch veränderten Mutanten, denen entweder eine oder drei der vier Glykosylierungstellen fehlten, Biodistributionsprofile aufwiesen, die dem des parentalen Protein ähneln. Im letzten Teil der Dissertation beschreiben wir das Klonieren und die therapeutischen Eigenschaften von neuen, auf Antikörpern basierenden Fusionsproteinen bestehend aus dem F8 Antikörper und murinem Interleukin-22, einem globulären Zytokin, das zur Interleukin-10 Familie gehört. Sowohl IL22-F8 als auch F8-IL22 akkumulierten selektiv im Entzündungsherd. Das Fusionsprotein, das die Zytokineinheit am N-Terminus trägt (IL22-F8) erzeugte bessere Resultate, sowohl die zielgerichtete Anreicherung im Gewebe wie auch die therapeutische Wirksamkeit betreffend. Mäuse, die mit IL22-F8 behandelt wurden zeigten im Vergleich zu Kontrolltieren einen schnelleren Rückgang der klinischen Symptome wie auch eine Verbesserung der makroskopischen und mikroskopischen Morphologie des Dickdarms. 4
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