Pulmonary Delivery of Biological Drugs

Abstract

In the last decade, biological drugs have rapidly proliferated and have now become an important therapeutic modality. This is because of their high potency, high specificity and desirable safety profile. The majority of biological drugs are peptide- and protein-based therapeutics with poor oral bioavailability. They are normally administered by parenteral injection (with a very few exceptions). Pulmonary delivery is an attractive non-invasive alternative route of administration for local and systemic delivery of biologics with immense potential to treat various diseases, including diabetes, cystic fibrosis, respiratory viral infection and asthma, etc. The massive surface area and extensive vascularisation in the lungs enable rapid absorption and fast onset of action. Despite the benefits of pulmonary delivery, development of inhalable biological drug is a challenging task. There are various anatomical, physiological and immunological barriers that affect the therapeutic efficacy of inhaled formulations. This review assesses the characteristics of biological drugs and the barriers to pulmonary drug delivery. The main challenges in the formulation and inhalation devices are discussed, together with the possible strategies that can be applied to address these challenges. Current clinical developments in inhaled biological drugs for both local and systemic applications are also discussed to provide an insight for further research.

Keywords: aerosol; inhalation; lung; monoclonal antibodies; therapeutic proteins.

Figure 1

The fate of inhaled biological drugs in the airways upon lung deposition. Following dissolution in the lining fluid, the biological drugs either act on the surface of the epithelial cells, or being taken up by the cells where they are metabolised or absorbed into the systemic circulation.

Figure 2

Transport and recycle of IgG in the lung epithelium by the FcRn-mediated pathway. IgG is taken up into FcRn-expressing epithelial cells via non-specific fluid-phase pinocytosis. IgG then binds to the transport receptor, FcRn, which is mainly distributed within the acidic endosomal vesicles in the cell. The Fc receptor binds to IgG with high affinity at low pH but shows no affinity at physiologic pH. FcRn with bound IgG is sorted into the sorting endosome, which either recycle or transcytose to the plasma membrane. Nonprotected IgG and proteins proceed to lysosomal proteolytic degradation. The near-neutral pH results in dissociation and release of IgG from FcRn into the extracellular fluid.

Figure 3

Schematic representation of different antibody fragments investigated for pulmonary delivery. (A) Conventional antibodies from mammals have Y-shape structure composed of two identical heavy and light chains. Each chain contains constant regions (CH1, CH2, CH3 and CL) and variable regions (VH and VL) that are held together by disulfide bonds. Members of the Camelidae family naturally produce a unique type of immunoglobulin that is devoid of light chains. These heavy chain-only antibodies (HCAbs) are formed by a single variable domain (VHH) and two constant domains; (B) Fab is an antibody fragment that can bind to antigens without Fc region; F(ab’)2 contains two Fab fragments linked together by disulfide bonds; (C) Single-chain fragment variable (scFv) is composed of variable domains of the heavy (VH) and light chains (VL) of human IgG, connected by a peptide linker; (D) Domain antibodies (dAbs) are antibody fragments derived from the variable domains of either the heavy or light chain of human IgG. Nanobody^® is the recombinant single-domain antibody derived from the HCAbs of Camelidae.

Figure 4

Structure of PEGylated protein and Fc-fusion protein. PEGylation is a chemical process involving the attachment of polyethylene glycol (PEG) chains to a molecule of interest through covalent binding or non-covalent complexation; Fc-fusion proteins are composed of the Fc domain of IgG genetically linked to a peptide or protein of interest. The first-generation Fc-fusion proteins are dimeric wherein an effector molecule is fused with each arm of the Fc fragment. The second-generation Fc-fusion proteins are monomeric wherein a single effector molecule is conjugated to one arm of the Fc fragment.