Abrégé

Provided a proximity-enabled reactive therapeutics (PERx) approach to generate covalent protein drugs. A latent bioreactive amino acid FSY was incorporated into human programmed cell death protein 1 (PD-1), which selectively reacted with a proximal histidine of human PD-L1 upon binding, enabling irreversible binding of PD-1 with PD-L1 in vitro, on cancer cells, and in tumor in mice. When administrated in humanized mouse models, the covalent PD-1 (FSY) exhibited robust antitumor effect over wildtype PD-1, achieving therapeutic efficacy equivalent to the FDA approved therapeutic monoclonal antibody atezolizumab. The PERx approach should provide a general method for converting interacting proteins into covalent protein drugs for high therapeutic efficacy.

Classes IPC  ?

• A61K 31/197 - Acides carboxyliques, p. ex. acide valproïque ayant un groupe amino les groupes amino et carboxyle étant liés à la même chaîne carbone acyclique, p. ex. acide gamma-aminobutyrique [GABA], bêta-alanine, acide epsilon-aminocaproïque ou acide pantothénique
• C07K 1/113 - Procédés généraux de préparation de peptides par modification chimique de peptides précurseurs sans changement de la structure primaire
• C07C 381/02 - Thiosulfates
• A61K 31/198 - Alpha-amino-acides, p. ex. alanine ou acide édétique [EDTA]
• A61P 35/00 - Agents anticancéreux