Delivering potent, stable, targeted and in vivo efficacious antibody–drug conjugates (ADCs) using pyridazinedione functional disulfide re-bridging reagents.

Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics on the market interact with only one target thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics emerged: bispecific antibodies.Bispecific formation using chemical methods is rare and low yielding and/or requires a large excess of one of the two proteins to avoid homodimerisation and heterogeneity. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalisation of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalised bispecifics with controlled loading in a modular and convergent manner.

Enabling oriented installation of non-engineered antibody fragments on nanoparticle surfaces to create next-generation antibody–nanoparticle conjugates.