Delivery systems for biologics

As a cornerstone of advanced therapeutics in modern medicine, biologics command significant attention in the search for effective treatments for human diseases. These biopharmaceuticals encompass a range of products including vaccines, recombinant therapeutic proteins, tissues, cells and gene therapies – all sourced from living organisms.¹ However, the entry of biologics into the pharmaceutical market is not without unique challenges, particularly when compared to small molecule drugs.

The market for biologics

The growing interest in biologics resonates with their impressive expansion on the global market. Indeed, in 2022, biologics constituted 40 percent of all US Food and Drug Administration (FDA) approved drugs, projecting a compound annual growth rate (CAGR) of 9.5 percent through 2027. This growth is accompanied by a substantial number of clinical trials, with close to 20,000 active investigations, involving about 9,500 new biologic treatments.^2,3

Biologics, unlike chemically synthesised drugs, are large molecules with complex formulations consisting of proteins and nucleic acids, or their genetically engineered fusion constructs, with a variety of complex molecular moieties from post-transcriptional or translational modification. Therefore, biologics identification and characterisation poses unparalleled challenges, as does their manufacturing processes and routes of administration while maintaining patient safety and clinical efficacy. Barriers that complicate biologics delivery include their susceptibility to enzyme degradation, serum protein interactions, electrostatic repulsion, neutralising immune reaction, and intracellular shielding like endosomal escape, among others. A possible solution could be tailoring biologics delivery systems to facilitate in vivo transport for on-target delivery of the safeguarded payload.^4,7

Delivery methods

One of the early successes in the delivery of biologics involved the use of viral constructs. Viral vectors, known for their unique ability to infiltrate and integrate genetic cargo into a host genome, are major platforms for payload delivery in gene therapy. By leveraging strategies that genetically modify DNA for gene and protein expressions, viral vectors demonstrate the ability to identify specific molecular targets. Furthermore, viral vectors can stimulate direct tumouricidal effects and simultaneously elicit immune-enhancing responses from the payloads designed for the malignant target and its tumour microenvironment (TME). These actions occur at both the delivery site and other systemic locations, thereby promoting an immunogenic response that leads to cancer cell death.

Moving towards oral delivery of biologics

Despite the FDA approval of only three new gene therapies in 2022,⁵ the promising outlook for the field is illustrated by the changing clinical trials landscape: with over 2,000 more gene therapies under active pre-clinical or clinical developments in the world by the end of the first quarter of 2023.⁶ Viral vectors, such as adeno-associated viruses, adenoviruses, herpes simplex and lentiviruses, are the most utilised in these trials. However, multiple technological challenges must still be overcome to unlock the full potential of viral‑vector‑mediated gene therapy.⁷ For example, reducing immunogenicity of the viral vectors and improving manufacturing process and capacity will be vital to the future success of gene therapies.

Introducing virus-like particles (VLPs) is an alternative strategy for enhancing the efficacy of gene therapy applications. VLPs are virus-derived materials and structures which are not capable of infecting the host cell and provide a robust means for both gene and protein delivery. Their small size also allows them to cross the blood-brain barrier, which is a vibrant field of research, especially in diseases of the central nervous system (CNS).^8,9

In contrast to virus-based vectors and VLPs, another viable approach is the use of non‑viral vectors for gene and protein delivery. The emergency use approval from the FDA of lipid nanoparticle- (LNP-) based mRNA vaccines during the COVID-19 pandemic attested the significance of LNPs. Notably, LNPs facilitate the transportation of large payloads, have limited immunogenicity, and allow for scalable manufacturing. Demonstrating promising results in delivering oligonucleotides and mRNA therapeutics, LNPs likely stand as the future preferred biologic drug carriers, especially for cancer vaccines or other innovative treatments. Although LNPs demonstrate great potential for in vivo delivery of biologics, significant challenges remain, including overcoming accumulation in the liver, maintenance of lasting protein expression, minimising immunological responses, and avoiding endosomal escape.^10,11

Various materials like nano-micelles, dendrimers, hydrogels and nanoemulsions are several of the actively explored polymer-based delivery systems. Despite issues of potential toxicity and biocompatibility, several polymers have advanced to clinical trial stages. For instance, use of the natural polymer cyclodextrin has pioneered delivery of siRNAs in trials at the clinics, underlining the increasing importance of this field.^4,6
Exosomes, the natural intercellular transporters, have been developed into a vector for biologics delivery. With intrinsic qualities like biocompatibility, low immunogenicity and acceptable toxicity, as well as excellent encapsulation and targeting abilities, exosomes are particularly useful in treating cancer and infectious diseases. Despite the perceived advantages of exosomes as carriers for biologics however, understanding their tissue or cellular transport mechanisms presents a significant issue in translational research. Standardising isolation, purification and storage processes are crucial areas for further improvement.¹²

Administration of biologics: key considerations

Bio-drug delivery systems are linked to the route of administration in clinics, which must be taken into consideration in clinical development, given the growing emphasis on patient-centric healthcare delivery. Oral administration is technically challenging for biologics due to their large size and unfavourable gastrointestinal tract environments. At present, most biologics are primarily administered via intratumoural or systemic, ie, intravenous, injections. However, the latest scientific research suggests that we are entering a new era of innovation in this field.

Orally administered robotic pills (RPs) herald a notable advancement in drug delivery technology. RPs can facilitate oral delivery through a small, painless, dissolvable needle packed with biotherapeutics, triggering a sequence of biochemical and biomechanical reactions that culminate in drug release within the small intestine. However, a precise release time is unpredictable for the encapsulated biologics, and it is not yet possible to administer biologics in high dose, mostly due to the limited capacity of the RPs as a delivery platform. Advancement of these oral medical devices is still in its infancy and further investigation is needed to ensure their effectiveness and safety in use for humans.¹³ Similarly, probiotic bacteria represent another innovative oral delivery platform in pre-clinical investigation and development. For example, bio-engineered probiotic bacteria can deliver a peptide to the intestinal tract, benefitting patients with rheumatoid arthritis.¹⁴ The success of these techniques could have a profound impact on the management of chronic inflammatory diseases.¹⁴

Developing future drug delivery systems

Although innovative engineered biologics carrier systems could improve treatment outcomes by assisting in on- or near-target delivery with a favourable therapeutic gradient and reduced toxicities, they are still very new and early in developmental cycles.
Artificial intelligence (AI) could help enhance mechanistic understanding of biologics delivery systems by providing a useful knowledge base of biological and biomechanical properties. This could be used to suggest plausible pharmacokinetic and pharmacodynamic behaviours of biologics related to deriving toxicity profile, and even predicting patient responses.¹⁵ Such progress is expected to result in significant improvements in the administration of biologics, ultimately improving patient and treatment outcomes. However, balancing effectiveness, immunogenicity, cost as well as patient convenience and acceptance remains essential. 

References

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2. Biologics market key drivers, segmentation, overview and outlook by 2032 [Internet] The Business Research Company. 2022. [cited 2024Jan]. Available from: https://www.thebusinessresearchcompany.com/report/biologics-global-market-report
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