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.

are co-founders and equity holders in Cell Biotherapy, Inc., Los Angeles, CA which supported this work. The other authors declare that they have no competing interests. The University of Southern California has a financial interest in Cell Biotherapy, Inc.

We hypothesized that imaging-based assessment of cellular proliferation in prostate cancer may improve tumor characterization. We therefore evaluated the biodistribution and effect of androgen on tumor uptake of the cellular proliferation imaging marker [18F]-2′-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU) in xenograft mouse models of human prostate cancer. Castrated and noncastrated athymic male mice were implanted with androgen-independent PC3 and androgen-sensitive CWR22 human prostate cancer cells. Dynamic microPET/CT imaging was performed for 1h followed by 10 minute static scans at 2h and 3h. Animals were sacrificed after imaging for biodistribution studies and immunohistochemical staining of tumors for androgen receptor and Ki-67/MIB expression. 18F-FMAU uptake was significantly higher in all major organs of the castrated animals in comparison to noncastrated mice with the highest uptake in liver and the lowest uptake in muscle and bone. When compared to PC3 tumors, CWR22 xenografts showed significantly higher tumor-to-muscle (2.56±0.30 vs. 1.99±0.30, p=0.008) and tumor-to-liver uptake ratios (1.72±0.12 vs. 1.26±0.17, p=0.0003) in the noncastrated animal at 3h time point. Androgen receptor and Ki-67/MIB expressions were higher in CWR22 than PC3 xenografts. Our initial preclinical observations suggest that there may be an association between androgen signaling and thymidine metabolism and that 18F-FMAU PET may be useful in prostate tumor characterization.

The identification and use of antibodies dominate the biologic, clinical diagnostic, and therapeutic landscapes. In particular, antibodies have become essential tools in a variety of protein analytical experiments and to study the disposition of biologic therapeutics. One emerging class of peptide biologics is known as the elastin-like polypeptides (ELPs), which are repetitive protein polymers inspired by human tropoelastin. A major limitation in the clinical translation of ELP biologics has been a lack of a monoclonal antibody (mAb) to characterize their identity during expression. To facilitate these studies, we successfully generated a new mAb that is specific toward ELPs and ELP fusion proteins. A purified antibody was evaluated in an ELISA, western blotting, and immunofluorescence assay. The optimal anti-ELP mAb proved to be highly reactive and specific toward ELPs. Moreover, they were able to detect ELPs with a variety of aliphatic guest residues. ELPs phase-separate in response to heating; furthermore, when incubated at a great excess of ELPs, the anti-ELP mAb partially blocks phase separation. These findings are direct evidence that novel murine mAbs can be raised against purified ELPs. This new reagent will enable purification, experimental detection, and characterization of these biopolymers.