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.