In vivo safety testing of antibody drug conjugates

Diplôme Master d'études avancées In vivo safety testing of antibody drug conjugates eng 2020-06-22 author Pretto Francesca 891965 director FitzGerald Rex Antibody Drug Conjugates (ADCs) are complex multi-domain biotherapeutics which combine, with the aid of a chemical linker, the tumor targeting properties of antibodies to the potent cytotoxicity of a selected small molecule (also called warhead or payload) to obtain novel pharmaceuticals for the treatment of cancer. ADCs are a rapidly growing class of pharmaceuticals with seven FDA-approved drugs already on the market and over eighty investigated at different stages of clinical development (1). The careful design of each of the ADC's building blocks allows to maximize anti-tumor efficacy while reducing the toxicity to healthy tissues. The preclinical characterization of these novel therapeutics requires the careful balance of the known requisites for small and biotechnology-derived molecules with a keen eye to the need of new effective treatments in the fight against cancer. From the analysis of official approval documents, available literature and current guidelines, this thesis will present the common features and peculiarities of the in vivo safety assessment of this emerging group of drugs. Moreover, this document will highlight the need for integrated and novel strategies for the preclinical evaluation of ADCs, stemming from their complex multi domain structure which sets them apart from both standard chemotherapy and antibody-based products. ADA Anti-Drug-Antibody ADC Antibody Drug Conjugate ADCC Antibody-Dependent Cell-mediated Cytotoxicity ADCP Antibody-Dependent Cellular Phagocytosis ADME Absorption Distribution Metabolism and Excretion ALCL Anaplastic Large-Cell Lymphoma AML Acute Myeloid Leukemia BBB Blood Brain Barrier CDC Complement Dependent Cytotoxicity CMC Chemistry Manufacturing and Control CYP Cytochrome P450 DAR Drug-to-Antibody Ratio EFD Embryofetal development EPR Enhanced Permeability and Retention FACS Fluorescence-Activated Cell Sorting FcRn neonatal Fc Receptor FcRγ Fc Gamma Receptor FDA Food and Drug Administration FIH First In Human HL Hodgkin Lymphoma HNSTD Highest Non-Severely Toxic Dose IC50 half maximal Inhibitory Concentration ICH International Conference on Harmonisation Ig Immunoglobulin IHC Immunohistochemistry ILD Interstitial Lung Disease MAb monoclonal Antibody MHC Major Histocompatibility Complex MMP Matrix Metalloproteinase MTD Maximum Tolerated Dose NHP Nonhuman Primates NOAEL No Observed Adverse Effect Level PEC Predicted Environmental Concentration PK Pharmacokinetic PPND Peri- and Postnatal development QWBA Quantitative whole-body autoradiography STD10 Severely Toxic Dose in 10% of the animals TI Therapeutic Index TMDD Target Mediated Drug Disposition UGT UDP-glucuronosyltransferase VEGFR Vascular Endothelial Growth Factor Receptor Dewey 610 Dewey 615 Master of Advanced Studies in Toxicology 31 Section des sciences pharmaceutiques 17 3 Faculté de médecine 2 false 33492072-81c2-4fdf-8d93-bf2ff8c88844 Master thesis Restricted MAS_thesis_FPretto-FINAL.pdf 435009 application/pdf restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine

Title	Published in	Access level	OA Policy	Year	Views	Downloads

In vivo safety testing of antibody drug conjugates				2020	86	10

Archive ouverte UNIGE

Pretto, Francesca