Brain delivery of BDNF and a monoclonal antibody for the treatment of neurodegenerative animal models

Abstract

There are a large number of protein-based therapeutics (biologics) that are FDA approved and available on the market for a number of diseases, and the number of biologics being approved every year has tripled in the past two decades. Biologics are highly attractive as therapeutic options due to their safety and efficacy; however, of all the marketed biologics, only several proteins are FDA approved for treatment of CNS. This is due to efficacy limitation of most proteins in the CNS. One of the reasons is due to the presence of the blood–brain barrier (BBB), which selectively limits protein drugs from entering the brain. Although the BBB is critical for things such as maintaining proper concentration of ions and preventing infection as well as harmful toxins from entering the brain, its selectivity makes it difficult to deliver diagnostic and therapeutic agents into the brain. Only a small fraction (i.e., 2%) of marketed small drugs has appreciable penetration into the CNS. Thus, there is a large unmet need to improve drug delivery to the brain for treatment of brain diseases such as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s, and brain tumors. Currently, drugs that are not able to cross the BBB are sometimes administered via direct cranial injection or cerebral spinal fluid infusion; however, these are relatively invasive methods and they increase the risk for CNS infections. The goals of this project were specifically to investigate (i) if BBB modulation via the cadherin cyclic peptide, ADTC5, could be used to deliver brain-derived neurotrophic factor (BDNF) across the BBB to treat an experimental autoimmune encephalomyelitis (EAE), a mouse model of MS; (ii) if ADTC5 could also be used to deliver BDNF to treat an aggressive mouse model for Alzheimer’s disease (i.e., APP/PS1 mice); and (iii) how ADTC5 can improve brain delivery a monoclonal antibody (mAbs) for evaluating its clearance from the brain in healthy mice. First, we observed that ADTC5 was able to significantly enhance the deposition of BDNF to have efficacies in the EAE and Alzheimer’s disease animal models. Compared to when BDNF was delivered alone or placebo, BDNF + ADTC5 improved clinical body scores and cognitive performance in EAE mice and APP/PS1, respectively. Additionally, both EAE and APP/PS1 mice that were treated with BDNF + ADTC5 showed increase levels of NG2 microglia, and EGR and ARC mRNA transcripts compared to BDNF alone or vehicle. In the EAE model, the NG2 glia was associated with increased levels of myelin. Second, we monitored monoclonal antibody (mAb) brain deposition and clearance after its brain delivery with ADTC5 peptide. In addition, the effect of ADTC5 in mAb depositions in other organs was also determined. We observed a rapid clearance of mAb from the brain after enhanced delivery by ADTC5 with two different phases. The estimated t1/2alpha and t1/2beta of IgG mAb were 0.34 ¬± 0.22 h and 65.50 ± 12.09¬ h, respectively. This clearance was heavily facilitated by the liver and ADTC5 did not affect antibody deposition into liver, spleen, kidney, lung, or heart. Overall, this project demonstrates a proof-of-concept that brain diseases can be effectively treated via brain delivery of therapeutic proteins using BBB modulation by cadherin peptides (e.g., ADTC5).