Engineering and pharmacology of blood-brain barrier-permeable bispecific antibodies.

The development and approval of antibody-based therapeutics have progressed rapidly over the past decade. However, poor blood-brain barrier (BBB) permeability hinders the progress of antibody therapies for conditions in which the target is located in the central nervous system (CNS). Increased brain penetration of therapeutic antibodies can be achieved by engineering bispecific antibodies in which one antibody binding specificity recognizes a BBB receptor that undergoes receptor-mediated transcytosis (RMT) from the circulatory compartment into brain parenchyma, and the second binding specificity recognizes a therapeutic target within the CNS. These bispecific antibodies can be built using various antibody fragments as "building blocks," including monomeric single-domain antibodies, the smallest antigen-binding fragments of immunoglobulins. The development of BBB-crossing bispecific antibodies requires targeted antibody engineering to optimize multiple characteristics of "BBB carrier" and therapeutic arms, as well as other antibody properties impacting pharmacokinetics and effector function. Whereas several BBB-crossing bispecific antibodies have been developed using transferrin receptor antibodies as BBB carriers, the principal obstacle for capitalizing on the future promise of CNS-active antibodies remains the scarcity of known, characterized RMT receptors which could be exploited for the development of BBB carriers. This chapter reviews the recent advances and guiding principles for designing, engineering, and evaluating BBB-crossing bispecific antibodies and discusses approaches to identify and characterize novel BBB-crossing antibodies and RMT receptors.