Opening the central nervous system (CNS) to antibody therapies would substantially improve our ability to selectively target neurological disease. However, brain uptake of antibodies is limited by the presence of the blood–brain barrier (BBB). Over the past 20 years, progress has been made in designing methods to improve uptake of antibodies via molecular engineering, with most attention being placed on utilizing the BBB's endogenous mechanisms to transport proteins into the brain, known as receptor-mediated transcytosis (RMT; Jones and Shusta, 2007). Nevertheless, challenges in both understanding the biology of BBB transport and in engineering antibodies to optimally cross the BBB remain. In particular, the majority of studies assessing RMT pathways at the BBB have relied on radiolabeled proteins. However, from a drug development standpoint, success is only achieved if antibody is delivered to the brain in sufficient quantities to be therapeutically beneficial. Thus, this experimental approach may be misleading, as trace doses do not assess the therapeutic capacity of a particular RMT pathway.

Transferrin, insulin, Apo-proteins, IGF-1, and leptin, are among an ever-increasing list of proteins that have been proposed to undergo RMT at the BBB. The transferrin/transferrin receptor (TfR) system, which mediates cellular uptake of iron, has been of particular interest as a pathway to increase uptake of biologics into the brain. Early studies with anti-TfR antibodies showed promise for the TfR pathway (Friden et al, 1991). Nevertheless, subsequent studies questioned how effective the TfR pathway is in driving CNS uptake of Tf itself (Crowe and Morgan, 1992), and also questioned the ability of anti-TfR antibodies to traverse the BBB and distribute throughout the brain (Moos and Morgan 2001). These, and subsequent studies, showed that anti-TfR antibodies largely remained trapped in the BBB vasculature and cast doubt on the TfR pathway as a route to transport therapeutic antibodies into the brain.

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