*Review* **Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives**

**Aida Kouhi, Vyshnavi Pachipulusu, Talya Kapenstein, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli \***

Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; kouhi@usc.edu (A.K.); pachipul@usc.edu (V.P.); talya.kapenstein@gmail.com (T.K.); peisheng@usc.edu (P.H.); aepstein@usc.edu (A.L.E.) **\*** Correspondence: lkhawli@usc.edu

**Abstract:** Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer's, and Parkinson's disease. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood–brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1–0.2% of injected dose) of circulating antibodies into the brain. This article reviews the various methods currently used for antibody delivery to the CNS at the preclinical stage of development and the underlying mechanisms of BBB penetration. It also describes efforts to improve or modulate the physicochemical and biochemical properties of antibodies (e.g., charge, Fc receptor binding affinity, and target affinity), to adapt their pharmacokinetics (PK), and to influence their distribution and disposition into the brain. Finally, a distinction is made between approaches that seek to modify BBB permeability and those that use a physiological approach or antibody engineering to increase uptake in the CNS. Although there are currently inherent difficulties in developing safe and efficacious antibodies that will cross the BBB, the future prospects of brain-targeted delivery of antibody-based agents are believed to be excellent.

**Keywords:** blood–brain barrier; antibody; pharmacokinetics; disposition; biochemical and physicochemical properties; Fc binding; receptor-mediated transcytosis; brain shuttle; molecular Trojan horse; transferrin
