Application of Next-Generation Maleimides (NGMs) to Site-Selective Antibody Conjugation

Site-selective antibody conjugation is widely recognized as a key strategy for the optimum construction of antibody-drug conjugates (ADCs). Achieving such bioconjugation directly onto native antibodies would represent the ideal solution, as it would afford greatly improved homogeneity whilst avoiding the need for genetic engineering, and even allow the repurposing of existing antibodies "off-the shelf." Here we describe a protocol for the use of next-generation maleimides (NGMs) for the selective modification of the four interchain disulfide bonds present in a typical IgG1 antibody format. These reagents retain the efficiency of classical maleimides whilst serving to rebridge each reduced disulfide bond, affording one attachment per disulfide. The approach is simple, uses readily available reagents, and generates robustly stable conjugates which are ideal for in vitro or in vivo applications. In addition to use in the construction of ADCs these reagents can also be used to develop antibody conjugates for imaging, bispecifics, and broadly for use across biology and medicine

The many faces of insulin-like peptide signalling in the brain

Central and peripheral insulin-like peptides (ILPs), which include insulin, insulin-like growth factor 1 (IGF1) and IGF2, exert many effects in the brain. Through their actions on brain growth and differentiation, ILPs contribute to building circuitries that subserve metabolic and behavioural adaptation to internal and external cues of energy availability. In the adult brain each ILP has distinct effects, but together their actions ultimately regulate energy homeostasis - they affect nutrient sensing and regulate neuronal plasticity to modulate adaptive behaviours involved in food seeking, including high-level cognitive operations such as spatial memory. In essence, the multifaceted activity of ILPs in the brain may be viewed as a system organization involved in the control of energy allocation. © 2012 Macmillan Publishers Limited. All rights reserved.Peer Reviewe