α-Amanitin-based Small Format-Drug Conjugates for Prostate Cancer Therapy: Enabling Anti-Tumor Activity by Tuning Pharmacokinetic Properties

Gallo F (2021)
Bielefeld: Universität Bielefeld.

Bielefelder E-Dissertation | Englisch
 
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Autor*in
Gallo, Francesca
Betreuer*in
Pahl, Andreas; Müller, Christoph
Abstract / Bemerkung
Antibody-Drug Conjugates (ADCs) based on antibodies as tumor-homing vehicles of cytotoxic drugs, represent a breakthrough in cancer treatment with seven approved products. High specific recognition of tumor-associated antigens provided by antibodies allows the preferential localization of the cytotoxic drug at the tumor site, reducing the systemic toxicity of conventional chemotherapy. While majority of the most advanced ADCs is directed against hematological cancers, treatment of solid tumors with ADCs remains still challenging. The unique physiology of a solid tumor and the large size of ADCs impair the penetration and the even distribution of these therapeutics in the tumor tissue. As format alternative to ADCs, Small Molecule-Drug Conjugates (SMDCs) which utilize small organic ligands as tumor-homing vehicles are recently gaining growing attention due to their potential better tumor-penetrating properties. The first part of the present study (Chapters 3-5) describes the design and preclinical characterization of a small library of SMDCs. The products herein described were designed to target prostate cancer cells by means of a small glutamate-urea-based ligand known as DUPA. DUPA binds with high affinity to Prostate Specific Membrane Antigen (PSMA), a validated target of virtually all prostate cancers. α-Amanitin, a natural toxin isolated from the green death cap mushroom Amanita phalloides, which acts as potent RNA polymerase II inhibitor of eukaryotic cells, was investigated as innovative SMDC drug payload. Variation of the linker and conjugation chemistry between the targeting moiety and the drug payload led to the first-generation of PSMA-targeting α-amanitin-based SMDCs. The most promising candidates selected from the initial screening of the in vitro activity were further characterized in vivo in murine models. The limited antitumor activity associated to their poor pharmacokinetic properties fuelled research into a variety of strategies to optimize the pharmacokinetic properties and increase the therapeutic efficacy of the PSMA-targeting α-amanitin-based SMDCs, which are described in the second part of this study (Chapters 6-9). The attempts led ultimately to the generation of a Small Molecule-Fc-Drug Conjugate (Fc-SMDC) by grafting a PSMA-targeting α-amanitin-based SMDC onto an IgG1-Fc fragment. Combination within a single platform of a small organic ligand with well-known targeting and internalization properties, a drug payload with unique mode of action and favourable physiochemical properties, and an Fc portion providing extended circulatory half-life led to an ADC-like therapeutic with outstanding antitumor activity, but yet much smaller than a conventional ADC.
Jahr
2021
Page URI
https://pub.uni-bielefeld.de/record/2955322

Zitieren

Gallo F. α-Amanitin-based Small Format-Drug Conjugates for Prostate Cancer Therapy: Enabling Anti-Tumor Activity by Tuning Pharmacokinetic Properties. Bielefeld: Universität Bielefeld; 2021.
Gallo, F. (2021). α-Amanitin-based Small Format-Drug Conjugates for Prostate Cancer Therapy: Enabling Anti-Tumor Activity by Tuning Pharmacokinetic Properties. Bielefeld: Universität Bielefeld. https://doi.org/10.4119/unibi/2955322
Gallo, F. (2021). α-Amanitin-based Small Format-Drug Conjugates for Prostate Cancer Therapy: Enabling Anti-Tumor Activity by Tuning Pharmacokinetic Properties. Bielefeld: Universität Bielefeld.
Gallo, F., 2021. α-Amanitin-based Small Format-Drug Conjugates for Prostate Cancer Therapy: Enabling Anti-Tumor Activity by Tuning Pharmacokinetic Properties, Bielefeld: Universität Bielefeld.
F. Gallo, α-Amanitin-based Small Format-Drug Conjugates for Prostate Cancer Therapy: Enabling Anti-Tumor Activity by Tuning Pharmacokinetic Properties, Bielefeld: Universität Bielefeld, 2021.
Gallo, F.: α-Amanitin-based Small Format-Drug Conjugates for Prostate Cancer Therapy: Enabling Anti-Tumor Activity by Tuning Pharmacokinetic Properties. Universität Bielefeld, Bielefeld (2021).
Gallo, Francesca. α-Amanitin-based Small Format-Drug Conjugates for Prostate Cancer Therapy: Enabling Anti-Tumor Activity by Tuning Pharmacokinetic Properties. Bielefeld: Universität Bielefeld, 2021.
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2021-06-02T13:57:40Z
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