TY  - THES
AB  - 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.
DA  - 2021
DO  - 10.4119/unibi/2956317
LA  - eng
PY  - 2021
TI  - DUPA α-Amanitin Conjugates  for Targeted Prostate Cancer Therapy - Optimization and Evaluation of In Vivo Potency
UR  - https://nbn-resolving.org/urn:nbn:de:0070-pub-29563178
Y2  - 2024-11-22T02:56:51
ER  -