Next generation maleimides enable the controlled assembly of antibody–drug conjugatesvianative disulfide bond bridging

Abstract

Highly homogeneous ADCs are generated by the efficient bridging of interchain disulfide bonds in trastuzumab, using next generation maleimides.

Site-selective in situ growth of fluorescent polymer–antibody conjugates with enhanced antigen detection by signal amplification

“…In contrast to Herceptin-SH, the inter-chain disulfide bridging was re-established in Herceptin-Br, so that it migrated as a loose single band. However, upon heating, a new band corresponding to half antibody (heavy chain plus light chain, H þ L) was observed for Herceptin-Br, indicating that the inter-heavy-chain disulfides were not completely re-bridged [31]. On the other hand, on reducing and heating SDS-PAGE (Fig.…”

“…On the other hand, on reducing and heating SDS-PAGE (Fig. S2), both Herceptin and Herceptin-SH migrated as two bands for the light (L) and heavy (H) chains, respectively; in contrast, Herceptin-Br migrated as multiple bands corresponding to L, [6,31], respectively, suggesting that Herceptin-Br was even more stable than Herceptin and Herceptin-SH under the reducing and heating conditions, presumably due to the more stable thioether bond than the disulfide bond. Note that the thioether bond formed can be broken or replaced by reducing agents [21].…”

Disulfide Conjugation Chemistry: A Mixed Blessing for Therapeutic Drug delivery?

“…For example, dibromomaleimide modified cytotoxic drugs have been linked to disulfide bonds on antibodies, allowing the preservation of stable linkages between the Fab and Fc regions [13]. The dibromomaleimide coupling strategy has also been applied to the conjugation of polymers to proteins.…”

Antibody Conjugates: From Heterogeneous Populations to Defined Reagents

“…In addition, the structure of the antibody remains intact and the ligand-to-antibody ratio can be tightly controlled [48,49]. Researchers in the labs of Chudasama, Baker and Caddick describe two different bridging approaches whereby they developed both a novel class of maleimides, designated as next generation maleimides, and successfully generated ADCs with all the aforementioned advantages [50,51] in addition to using pyridazinedione derivatives to generate dual-modified ADCs [52]. This technology can be used to site-specifically attach two different functionalities onto an antibody while benefiting from the aforementioned advantages of bridging approaches.…”