Translational Approaches for Brain Delivery of Biologics via Cerebrospinal Fluid.

Delivery of biologics via cerebrospinal fluid (CSF) has demonstrated potential to access the tissues of the central nervous system (CNS) by circumventing the blood-brain barrier and blood-CSF barrier. Developing an effective CSF drug delivery strategy requires optimization of multiple parameters, including choice of CSF access point, delivery device technology, and delivery kinetics to achieve effective therapeutic concentrations in the target brain region, whereas also considering the biologic modality, mechanism of action, disease indication, and patient population. This review discusses key preclinical and clinical examples of CSF delivery for different biologic modalities (antibodies, nucleic acid-based therapeutics, and gene therapy) to the brain via CSF or CNS access routes (intracerebroventricular, intrathecal-cisterna magna, intrathecal-lumbar, intraparenchymal, and intranasal), including the use of novel device technologies.

In vitro model for predicting bioavailability of subcutaneously injected monoclonal antibodies.

Monoclonal antibodies (mAbs), which are now more frequently administered by subcutaneous (SC) injection rather than intravenously, have become a tremendously successful drug format across a wide range of therapeutic areas. Preclinical evaluations of mAbs to be administered by SC injection are typically performed in species such as mice, rats, minipigs, and cynomolgus monkeys to obtain critical information regarding formulation performance and prediction of PK/PD outcomes needed to select clinical doses for first-in-human studies. Despite extensive efforts, no preclinical model has been identified to date that accurately predicts clinical outcomes for these SC injections.

Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates.

Background And Purpose: The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood-brain barrier. I.c.

Evaluation of the Toxicity of Intravitreally Injected PLGA Microspheres and Rods in Monkeys and Rabbits: Effects of Depot Size on Inflammatory Response.

Purpose: Poly(lactic-co-glycolic) acid (PLGA) inserts have been successfully developed for the treatment of posterior eye disease as a means of reducing injection frequency of intravitreally administered therapeutics. PLGA microspheres are also of interest for the delivery of intravitreal drugs, since they offer the advantage of being easily injected without surgical procedures or large injectors.

Methods: In the current study, the toxicity of PLGA microspheres and rods was investigated in nonhuman primates (NHPs) and rabbits.

A novel in vitro method to model the fate of subcutaneously administered biopharmaceuticals and associated formulation components.

Subcutaneous (SC) injection is becoming a more common route for the administration of biopharmaceuticals. Currently, there is no reliable in vitro method that can be used to anticipate the in vivo performance of a biopharmaceutical formulation intended for SC injection. Nor is there an animal model that can predict in vivo outcomes such as bioavailability in humans.

Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration.

Subcutaneous (SC) delivery is a common route of administration for therapeutic monoclonal antibodies (mAbs) with pharmacokinetic (PK)/pharmacodynamic (PD) properties requiring long-term or frequent drug administration. An ideal in vivo preclinical model for predicting human PK following SC administration may be one in which the skin and overall physiological characteristics are similar to that of humans. In this study, the PK properties of a series of therapeutic mAbs following intravenous (IV) and SC administration in Göttingen minipigs were compared with data obtained previously from humans.

Sustained release formulations of rhVEGF₁₆₅ produce a durable response in a murine model of peripheral angiogenesis.

Local delivery of therapeutic angiogenic agents that stimulate blood vessel formation represents a promising strategy for the treatment of peripheral vascular disease (PVD). At present, requirements for temporal and spatial parameters for localized delivery are unclear, with a variety of sustained delivery approaches being examined. Two polymer-based sustained formulations containing the 165 amino acid isoform of human recombinant vascular endothelial growth factor-A (rhVEGF(165)) were evaluated for their potential application in the treatment of PVD following intramuscular injection.

Local tissue distribution and cellular fate of vascular endothelial growth factor (VEGF) following intramuscular injection.

Vascular endothelial growth factor (VEGF) is an extracellular matrix (ECM)-binding growth factor capable of driving neovascularization. VEGF can potentially be applied clinically via intramuscular (IM) injection to correct local ischemia associated with peripheral artery disease (PAD). As interactions with ECM elements and cognate receptors at the site of an IM injection define the local biology of VEGF and previous studies have only focused on systemic distribution measurements, we have established a method to monitor the local VEGF distribution and fate.

Magnetic resonance angiography reveals therapeutic enlargement of collateral vessels induced by VEGF in a murine model of peripheral arterial disease.

Purpose: To quantify spontaneous and therapeutic arteriogenesis in vivo in a murine model of peripheral arterial disease using magnetic resonance angiography.

Materials And Methods: Male, 8-12-week-old, C57/BL6 mice underwent femoral artery ligation; 21 days later, 2 mg/kg recombinant murine VEGF165, formulated for slow release, was injected into the ipsilateral gastrocnemius. The spontaneous (following ligation) and therapeutic (following vascular endothelial growth factor (VEGF)) formation of collateral vessels was quantified using 3D magnetic resonance angiography on a small-bore 4.

Formulation and delivery issues for monoclonal antibody therapeutics.

Antibodies can have exquisite specificity of target recognition and thus generate highly selective outcomes following their systemic administration. While antibodies can have high specificity, the doses required to treat patients, particularly for a chronic condition, are typically large. Fortunately, advances in production and purification capacities have allowed for the exceptionally large amounts of highly purified monoclonal antibodies to be produced.

Emerging technologies that overcome biological barriers for therapeutic protein delivery.

In the past decade, genomic research and the nascent field of proteomics have exponentially increased the number of potential protein therapeutic molecules for treating medical needs that were previously unmet. To realise the full clinical potential of many of the novel protein drug entities arising from these intense research efforts, emerging protein delivery technologies may be required. Advanced delivery technologies may offer the ability to overcome biochemical and anatomical barriers to protein drug transport, without incurring adverse events, to deliver the agent(s) at a certain desired rate and duration, to protect therapeutic macromolecules from in situ or systemic degradation, as well as increase their therapeutic index by targeting the drug action to a specific site.

Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover.

Several growth factors are expressed in distinct temporal and spatial patterns during fracture repair. Of these, vascular endothelial growth factor, VEGF, is of particular interest because of its ability to induce neovascularization (angiogenesis). To determine whether VEGF is required for bone repair, we inhibited VEGF activity during secondary bone healing via a cartilage intermediate (endochondral ossification) and during direct bone repair (intramembranous ossification) in a novel mouse model.

Bacterial toxins as tools for mucosal vaccination.

Several studies have demonstrated that the biological properties of secreted bacterial toxins could be harnessed for the induction of mucosal and systemic immunity following application at epithelial surfaces. Although the properties and potential application of several of these toxins will be discussed in this review, special focus will be placed on Pseudomonas aeruginosa exotoxin A (PE). A non-toxic form of PE (ntPE) into which antigenic epitopes can be integrated appears to be a particularly promising vaccination tool, which is able to cross the polarized epithelia of the gastrointestinal, respiratory and reproductive tracts and selectively target macrophages and dendritic cells.