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A new generation of neurobiological drugs engineered to overcome the challenges of brain drug delivery.

A new generation of multifunctional fusion proteins presents a potential solution to overcome the challenges associated with brain drug delivery and development of treatments for neurological disorders, including stroke, Alzheimer's disease, Parkinson's disease and inherited mucopolysaccharidosis. These biotherapeutics are engineered i) to cross the blood-brain barrier (BBB) following i.v. administration and ii) to produce a brain therapeutic effect. These fusion proteins are comprised of both a transport and a therapeutic domain. The transport domain is a monoclonal antibody (MAb) directed to an exofacial epitope of the BBB human insulin receptor (HIR), which uses the BBB endogenous insulin transport system to gain access to the brain via receptor-mediated transcytosis without interfering with the normal transport of insulin. Both human-chimeric and fully humanized versions of the anti-human HIRMAb have already been produced. The therapeutic domain of these fusion proteins consists of the peptide or protein of interest fused to the carboxyl terminus of the C(H)3 region of the heavy chain of the anti-human HIRMAb. A variety of HIRMAb fusion proteins were engineered aiming at the development of therapeutics for the central nervous system (CNS), i.e., stroke and Parkinson's disease, as in the case of HIRMAb-BDNF and HIRMAb-GDNF, respectively, HIRMAb-IDUA for the treatment of Hurler's disease, HIRMAb-A beta single chain antibody for passive immunotherapy of Alzheimer's disease, and HIRMAb-avidin as delivery system for biotinylated drugs, like siRNAs. The multifunctionality of these fusion proteins has been validated in preclinical work, including brain update in primates. Pending further development into pharmacological and toxicological studies, and clinical trials, members of the biotherapeutic family discussed in the present review, designed to overcome the brain drug delivery hurdle, are positioned to become a new generation of neuropharmaceutical drugs for the treatment of human CNS disorders.