Standard antibody drugs are designed to specifically target a single antigen. However, many complex diseases are driven by multiple factors, so inhibiting a single target may fail to achieve significant efficacy. For example, in some diseases cells may respond to the inhibition of one receptor by producing more of a second receptor to circumvent the impact of the drug.
Bispecific antibodies aim to treat multifaceted, complex diseases by engaging two disease targets with one molecule. While natural antibodies have two targeting arms that bind to the same target antigen, bispecific antibodies are engineered hybrid molecules with two distinct binding domains that target two distinct antigens.
One challenge in making bispecific antibodies is getting cells to assemble the pieces of the antibody correctly. Antibodies are modular in nature. When cells are asked to incorporate subunits from two different antibodies into one structure, they generate 10 configurations, and just one has the correct and functional format (see insert). To solve this problem, scientists at Amgen have engineered antibodies with positive and negative electrical charges inserted at key points (indicated by + and - signs). This approach ensures that the correct subunits are attracted to each other while incorrect pairings are repulsed. The key result is a process that generates fully functional bispecific molecules, a major step in advancing this highly promising drug modality.