DUPA α-Amanitin Conjugates for Targeted Prostate Cancer Therapy - Optimization and Evaluation of In Vivo Potency

Korsak B (2021)
Bielefeld: Universität Bielefeld.

Bielefelder E-Dissertation | Englisch
 
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Autor*in
Korsak, Barbara
Betreuer*in
Hechler, Torsten; Pahl, Andreas; Sewald, NorbertUniBi
Abstract / Bemerkung
Prostate cancer remains the 4th most common cancer worldwide and the 2nd most common cancer in men. The Prostate Specific Membrane Antigen (PSMA) attracted a great attention as a target for the development of personalized therapeutics. Out of two PSMA targeted antibody-drug conjugates (ADCs) in clinical development none up to the moment reached the market approval due to limited efficacy or dose limiting toxicities. One of the main limitations in the use of ADCs in solid tumor therapy seems to be restrained tumor penetration due to the high molecular size of this class of therapeutics. In this work a library of small molecule drug conjugates (SMDCs) as an alternative for large molecular ADCs was developed and tested in vitro and in vivo. As a targeting moiety providing PSMA specificity the well-known PSMA ligand 2- [3-(1, 3-dicarboxy propyl) ureido]pentanedioic acid (DUPA) was used. The targeting moiety was followed by supporting spacer providing DUPA positioning in the PSMA active site and enabling its conjugation to a cytotoxic payload α-amanitin which is the inhibitor of RNA Polymerase II. The inhibition of RNA Polymerase II represents a completely new mode of action distinct to other toxins currently used for ADCs and SMDCs development. The most potent DUPA-α-amanitin conjugates were identified: HDP 30.2284 (bearing Val-Ala-PAB linker), HDP 30.2301 (bearing C6 non-cleavable linker) and HDP 30.2618 (bearing disulfide mono-hindered linker). Despite of an excellent in vitro profile, the lead SMDCs have shown only limited in vivo efficacy due to their very short half-life and limited tumor accumulation. In order to improve pharmacokinetic properties, the DUPA targeting moiety and the toxin were conjugated to an Fc portion of human IgG. DUPA-Fc-αamanitin conjugate showed slightly lower in vitro activity compared to the SMDCs. In vivo a significantly prolonged half-life and complete tumor remission in PSMA positive LNCaP xenograft model was observed. These results indicate that for highly hydrophilic toxin such as α-amanitin the gradual tumor delivery and accumulation over time is essential for sustainable anti-tumor activity. Describe herein novel DUPA-Fc-α-amanitin conjugate enriches the current landscape of ADCs based on the scaffold with a molecular weight being approximately 60 % smaller than full format IgG. Additionally, DUPA-Fc-α-amanitin retains prolonged half-life which is characteristic for antibodies. Moreover, proposed herein Fc-small molecule-toxin platform creates the opportunity to optimize small-molecule-toxin conjugates with sub-optimal pharmacokinetic profile.
Jahr
2021
Page URI
https://pub.uni-bielefeld.de/record/2956317

Zitieren

Korsak B. DUPA α-Amanitin Conjugates for Targeted Prostate Cancer Therapy - Optimization and Evaluation of In Vivo Potency . Bielefeld: Universität Bielefeld; 2021.
Korsak, B. (2021). DUPA α-Amanitin Conjugates for Targeted Prostate Cancer Therapy - Optimization and Evaluation of In Vivo Potency . Bielefeld: Universität Bielefeld. https://doi.org/10.4119/unibi/2956317
Korsak, B. (2021). DUPA α-Amanitin Conjugates for Targeted Prostate Cancer Therapy - Optimization and Evaluation of In Vivo Potency . Bielefeld: Universität Bielefeld.
Korsak, B., 2021. DUPA α-Amanitin Conjugates for Targeted Prostate Cancer Therapy - Optimization and Evaluation of In Vivo Potency , Bielefeld: Universität Bielefeld.
B. Korsak, DUPA α-Amanitin Conjugates for Targeted Prostate Cancer Therapy - Optimization and Evaluation of In Vivo Potency , Bielefeld: Universität Bielefeld, 2021.
Korsak, B.: DUPA α-Amanitin Conjugates for Targeted Prostate Cancer Therapy - Optimization and Evaluation of In Vivo Potency . Universität Bielefeld, Bielefeld (2021).
Korsak, Barbara. DUPA α-Amanitin Conjugates for Targeted Prostate Cancer Therapy - Optimization and Evaluation of In Vivo Potency . Bielefeld: Universität Bielefeld, 2021.
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2021-07-19T09:50:02Z
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