Titel (eng)

Rabbit derived VL single-domains as promising scaffolds to generate antibody-drug conjugates

Autor*in

Ana S. André   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Frederico Aires-da-Silva   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Luís Tavares   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Solange Gil   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Pedro M. P. Gois   Universidade de Lisboa

Joao Goncalves   Universidade de Lisboa

Miguel Castanho   Universidade de Lisboa

João D. G. Correia   Universidade de Lisboa

Lurdes Gano   Universidade de Lisboa

Barbara Rütgen   University of Veterinary Medicine Vienna

Berta São Braz   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Belmira Carrapiço   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Gonçalo Vicente   Universidade de Lisboa

Soraia Oliveira   Technophage SA

Vera Neves   Universidade de Lisboa

Marco Cavaco   Universidade de Lisboa

João P M António   Universidade de Lisboa

Joana Inês Carvalho   University of Lisbon

Pedro Bule   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Sara Nogueira   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Sandra Aguiar   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Joana N. R. Dias   University of Lisbon / Associate Laboratory for Animal and Veterinary Sciences

Verlag

Nature Portfolio

Beschreibung (eng)

Antibody-drug conjugates (ADCs) are among the fastest-growing classes of therapeutics in oncology. Although ADCs are in the spotlight, they still present significant engineering challenges. Therefore, there is an urgent need to develop more stable and effective ADCs. Most rabbit light chains have an extra disulfide bridge, that links the variable and constant domains, between Cys80 and Cys171, which is not found in the human or mouse. Thus, to develop a new generation of ADCs, we explored the potential of rabbit-derived VL-single-domain antibody scaffolds (sdAbs) to selectively conjugate a payload to Cys80. Hence, a rabbit sdAb library directed towards canine non-Hodgkin lymphoma (cNHL) was subjected to in vitro and in vivo phage display. This allowed the identification of several highly specific VL-sdAbs, including C5, which specifically target cNHL cells in vitro and present promising in vivo tumor uptake. C5 was selected for SN-38 site-selective payload conjugation through its exposed free Cys80 to generate a stable and homogenous C5-DAB-SN-38. C5-DAB-SN-38 exhibited potent cytotoxicity activity against cNHL cells while inhibiting DNA-TopoI activity. Overall, our strategy validates a platform to develop a novel class of ADCs that combines the benefits of rabbit VL-sdAb scaffolds and the canine lymphoma model as a powerful framework for clinically translation of novel therapeutics for cancer.

Sprache des Objekts

Englisch

Datum

2023

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Therapeutic Activity; Next-Generation; Strategies; Selection; Peptide

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