Leveraging the attributes of biologics and small molecules, and releasing the bottlenecks: a new wave of revolution in drug development

KEYWORDS:

• Biologics
• small molecules
• proteins
• antibody-drug conjugates
• peptides
• monoclonal antibodies
• lymphatic circulation
• drug development
• receptor-mediated drug disposition
• antibody fragments

Sound strategy starts with having the right goal. – Michael Eugene Porter, a leading authority on competitive strategy.

Having a sound strategy is obligatory to success, and the starting point is to have a noble goal in mind. Without doubt, one of our universal goals is to alleviate human illnesses through drug development. The discovery of penicillin by Alexander Fleming in 1928 elevated humans’ health from a daunting ‘dark age’ to the current era. Nevertheless, up to the present, of the roughly 30,000 unique protein sequences of the human proteome, only 1% has been successfully targeted [1]. The situation is aggravated by the rise in the standard of living where humans are living longer and more susceptible to diseases. Although the number of US approval for new molecular entities in 2015 (45) is the second highest in history, the number of submissions has been flat according to the US FDA. Because of unmet medical needs, the call for a new revolution is warranted.

For a start, it is critical to elucidate the attributes of available molecular entities, comprising of conventional small molecules (SMs), and biologics as new comers. Numerous articles have been written regarding biologics versus SMs, especially in the discovery setting [2–5]. However, an article geared toward advancing drug development from a clinical perspective is lacking. The aim here is to leverage the potentials of biologics and SMs, and to provide initiatives for navigating critical hindrances, in order to galvanize drug development.

The ascension of biologics

Advances in biotechnology permit large-scale syntheses of biologics in a cost-effective manner. Traditionally, treatments of human diseases have been dominated by SMs (molecular masses < 1000 g/mol or 1 kilodalton [kDa]). With the advent of biotechnology about 35 years ago, and after the completion of the Human Genome Project two decades later, the first humanized insulin (5.8 kDa) became available in 1982. This milestone was followed by the approvals of many more biologics ranging from a few kilodalton to several hundred times more. Among the biologics, larger proteins such as monoclonal antibodies (mAbs; >10 kDa) and smaller peptides (1 to <10 kDa, or containing <100 amino acids) are ubiquitous in biology. Most proteins consist of amino acids, sugars, or nucleotide bases that fold into unique three-dimensional structures. Peptides also have amino acid chains, but are intermediates between SMs and proteins, and display little tertiary structures.

Attributes in physicochemical properties

Biologics are generally polar, heat sensitive, readily degraded (except long-lived entities like monoclonal antibodies), and membrane impermeable. A large proportion of pharmacological targets are embedded and are inaccessible to biologics. This is particularly true for the central nervous system (CNS) drugs. The presence of tight junctions of the blood–brain barrier prevents the passage of molecules >600 Da and results in restricting up to 98% of SMs and practically all biologics [3]. Attempts to utilize special delivery vectors or relatively uncharacterized membrane transporters used to carry endogenous macromolecules are ongoing.

For oral absorption of SMs, permeability through intestinal epithelium is mostly mediated by a combination of passive diffusion and paracellular transport [6]. However, nearly all biologics are orally inactive due to their high molecular masses and intrinsic instabilities.

Attributes in efficacy and safety

The main advantages of biologics over SMs are their high specificity and low toxicity, while SMs are more promiscuous. SMs bind with targets like G-protein-coupled receptors, ligand-gated ion channels, and receptor tyrosine kinases on the extracellular or intracellular domains used by endogenous substrates. In terms of safety, biologics are known to cause less serious adverse events. One major exception is immunogenicity, where the efficacy, safety, and disposition of biologics can be affected.

Absorption, distribution, and elimination

SMs are distributed via the blood circulation. A sluggish (by 100–500 times) lymphatic system becomes prominent as molecular masses increase (e.g. >10 kDa) [4,5]. Larger biologics distribute via both the blood and the lymphatic systems, and move transcellularly by convective transport, receptor-mediated endocytosis, phagocytosis, and fluid-phase pinocytosis [7]. Consequently, larger biologics have longer half-lives, limited volumes of distribution, and longer times to peak concentrations than for SMs.

Drug disposition of nearly all SMs are mediated by nontargeted organs, through cytochrome or non-cytochrome metabolisms, renal filtration, or fecal excretion. Due to tight target interactions, drug dispositions of biologics are directly affected by their binding (receptor-mediated drug disposition) [4,7]. Among them are the clearances of biologics by proteases and peptidase. The resultant remnants of biologics are mostly recycled, while some are secreted into bile, excreted into feces, or filtered into urine (<70 kDa) as small components [8].

Drug–drug interaction potential

Drug–drug interaction can occur for SMs, subsequent to the presence of concomitant drugs that affect their metabolism, transport, or elimination pathways. Traditional drug–drug interactions are less frequent for biologics, since they undergo metabolism and elimination as the endogenous substrates. Nevertheless, cytokine-mediated changes in drug metabolizing enzymes are well documented, and drug–biologic interaction should be assessed when the biologics influence the expression of metabolic enzymes [5].

Promises of biologics

The potentials for biologics, which include protein–protein interactions (PPIs), gene editing/silencing, and cell-based therapies, including SiRNAs, zinc finger nucleases, TALEN®, and CRISPR/Cas9 system, remain to be fully harnessed. Glybera®, the first gene therapy that received the European Medicines Agency authorization in 2012 is a test case, as it has yet to be approved by the FDA.

Three favorable subclasses of biologics with bright potentials are highlighted in the following sections.

Peptides

In spite of the advantages of a peptide over a larger protein such as easier in synthesis, lower immunogenicity, and higher membrane permeability, the market size of peptides remains small. The awaited breakthroughs include viable noninvasive administrations [6] and CNS deliveries [9]. For noninvasive treatments, oral delivery seems to be the holy grail, as shown by the disappointing sales of the inhaled insulin Afrezza® for the first 9 months in 2015 (5 million euros).

Antibody–drug conjugates and antibody fragments

The 1–2 punch ability of antibody–drug conjugate (ADC) to incorporate specific mAbs and SMs as payloads is attractive [10], as exemplified by two FDA approvals, brentuximab vedotin (149–152 kDa) and trastuzumab emtansine (149 kDa). The approval of an antibody-fragment-antigen binding fragment (certolizumab pegol; 40 kDa) validates that fragments or single-domain antibody with lower molecular mass and immunogenicity can retain antibody activities [11,12].

Fusion proteins

Fusion proteins are an area of intense research. An increasing number of fusion protein have been constructed in the past few years, including multifunctional enzymes and protein switches [8,13].

Resurgence of small molecules

SMs have regrettably been sidelined when compared to biologics. In reality, SMs are good enzyme inhibitors and allosteric modifiers, and can target intracellular receptors in the cytosols, nuclei, and CNS.

Clinical applications of PPI are dominated by mAbs. With the advances in pharmacogenomics, the scenario could change following the approvals of two SMs: maraviroc (514 Da) and tirofiban (441 Da). Notably, recent advances in computational approach reveal that SMs are able to bind to specific interfaces of proteins with relatively high affinities [1,14,15]. Importantly, SMs can modulate the so-called ‘intrinsically disordered protein regions’ associated with neurodegenerative diseases, cancer, diabetes, and cardiovascular disease [16].

Overcoming drug development hindrances

Other than technological breakthroughs, we believe that a quantum leap in drug development of biologics and SMs is feasible through international collaborations and legislature changes. A global system devoid of uncoordinated processes and commercial competitiveness is crucial [17]. Recently, a number of initiatives have been proposed/implemented. However, a global execution of these initiatives spearheaded by more influential entities is essential. A recent announcement of $1 billion allocation for cancer research by US President Obama is a commendable example. There is no alternative other than to put a higher priority in medical research.

A number of proposals are outlined below:

• Digital empowerment and the creation of centralized ‘big data’. With digital advances in robust bioinformatics and machine learning systems, it is now feasible for wider initiatives such as disease registries, online patient enrollments, and real-time trial readouts. These changes will provide more cell lines, predictive animal models, and biomarkers for in vitro and in vivo translation, and facilitate clinical trials. These advances can be exploited to avert delays during health crises (e.g., Ebola and Zika pandemics).

• New disease nomenclature. This is to be based on molecular aberrations and not on disease locations and signs/symptoms. Although further comprehension is vital, many seemingly diverse diseases possess common underlying etiologies/links and can be classified accordingly.

• Precompetitive data sharing. Through public–private enterprise, valuable chemical-genetic data held by private enterprises can be made accessible [18]. A legislative change to galvanize this paradigm shift is indispensable.

• Repurposing compounds. With high risk in drug development, greater than 99% of starting compounds fail. Another piece of legislature change is required to free up large databases.

• Accelerate dissemination of medical information. A wider involvement of global communities will be necessary, via medical clearing houses, open-access journals, and health authorities.

• Quantitative systems pharmacology. Pooled resources to generate in silico disease modeling and virtual patients will be needed for real-life translation.

Conclusion

A new wave of drug development is realizable with multi-prong approaches as described above. Through a better leverage of the potentials of biologics and SMs, and concerted efforts to remove bottlenecks and legislative barriers, an exponential acceleration of drug development is feasible. With more effective drug therapies, the sequelae of human diseases will be substantially better.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgements

We are grateful to Dr. Honghui Zhou, Johnson and Johnson, and Dr. Yanfeng Wang, Ionis Pharmaceuticals, for their critical comments.