Optimizing Early Clinical Investigations in Cancer Immunotherapy: The Translational Journey of RG6292, a Novel, Selective Treg-Depleting Antibody.
Clin Pharmacol Ther
; 2024 May 20.
Article
em En
| MEDLINE
| ID: mdl-38769868
ABSTRACT
The multifaceted IL-2/IL-2R biology and its modulation by promising therapeutic agents are highly relevant topics in the cancer immunotherapy field. A novel CD25-Treg-depleting antibody (Vopikitug, RG6292) has been engineered to preserve IL-2 signaling on effector T cells to enhance effector activation and antitumor immunity, and is currently being evaluated in the clinic. The Entry into Human-enabling framework described here investigated the characteristics of RG6292, from in vitro quantification of CD25 and RG6292 pharmacology using human tissues to in vivo assessment of PK/PD/safety relationships in cynomolgus monkeys as non-human primate species (NHP). Fundamental knowledge on CD25 and Treg biology in healthy and diseased tissues across NHP and human highlighted the commonalities between these species in regard to the target biology and demonstrated the conservation of RG6292 properties between NHP and human. The integration of in vitro and in vivo PK/PD/safety data from these species enabled the identification of human relevant safety risks, the selection of the most appropriate safe starting dose and the projection of the pharmacologically-relevant dose range. The first clinical data obtained for RG6292 in patients verified the appropriateness of the described approaches as well as validated the full clinical relevance of the projected safety, PK, and PD profiles from animal to man. This work shows how the integration of mechanistic non-clinical data increases the predictive value for human, allowing efficient transition of drug candidates and optimizations of early clinical investigations.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Clin Pharmacol Ther
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
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