Divinylpyrimidine reagents generate antibody–drug conjugates with excellent in vivo efficacy and tolerability

Abstract

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first...

The use of bromopyridazinedione derivatives in chemical biology

“…A plethora of exciting reagents and technologies exist that can facilitate the selective modification of cysteine residues and disulfide bonds, each displaying a unique set of properties and associated advantages and disadvantages. [13][14][15][16][17][18][19][20][21] Amongst some of the most popular highly reactive cysteine-targeting technologies (e.g. maleimide and maleimide derivatives) issues can arise with regard to bioconjugate stability (i.e.…”

All-in-one disulfide bridging enables the generation of antibody conjugates with modular cargo loading

“…[29][30][31] These linkers contain two cysteine-reactive groups that may undergo reaction with reduced interchain disuldes in an IgG molecule to effect covalent rebridging of the antibody chains in a siteselective fashion. Next-generation maleimides (NGMs), 32,33 pyridazinediones, 34 bissulfones, 35 divinylpyrimidine (DVP) [36][37][38][39] and a variety of other reagents [40][41][42][43][44] have been used to modify antibodies in this way. However, the utility of this approach is currently hampered by the formation of fragmented "halfantibody" species during bioconjugation, which is the result of non-native intrachain cross-linking of the cysteine residues in the hinge region of the antibody (Fig.…”

Bioorthogonal site-selective conjugation of fluorescent dyes to antibodies: method and potential applications

“…2,4 Several re-bridging strategies and agents have been developed, including bissulfones, 7,8 divinylsulfonamides, 9 arylene dipropiolonitriles (ADPN), 10 dibromomethyl heterocycles (C-Lock™), 11 dichloroacetone, 12 next-generation maleimides, 13–15 pyridazinediones 16–22 and divinylpyrimidines. 23–25…”

“…2,4 Several re-bridging strategies and agents have been developed, including bissulfones, 7,8 divinylsulfonamides, 9 arylene dipropiolonitriles (ADPN), 10 dibromomethyl heterocycles (C-Lock™), 11 dichloroacetone, 12 next-generation maleimides, [13][14][15] pyridazinediones [16][17][18][19][20][21][22] and divinylpyrimidines. [23][24][25] Immunouorescence applications in general require uorescently labelled antibodies. Detection of the cellular target can either be achieved directly, using a primary labelled antibody, or indirectly, by using a secondary labelled antibody that recognises the primary (unlabelled) one.…”