Which protein(s) would be interesting to develop as long-acting injectables?

An urban legend from the height of the space race in the 1960s, tells of NASA engineers spending millions of dollars and many years developing a pen that functions at zero gravity, while, their Soviet colleagues opted for using pencils. Although fictional, this story reminds us of the value of simple, feasible solutions that often get overlooked.

Protein conjugation and derivatization approaches, such as PEGylation, albumin fusion, and Fc-fusion, are currently used to extend drug–half-life¹. These techniques enable less frequent administration of most mAbs, enzymes and other protein drugs while achieving therapeutic concentrations; by this, patient compliance is dramatically improved. What still remains an unmet need is a further limitation of drug toxicity alongside increased efficacy¹. A substantial amount of effort is focused on developing targeted "golden bullet" therapies, such as antibody-drug conjugates or peptide targeting. To date, only several such targeted therapeutics demonstrate clinical benefits.

In this essay, I propose to take a step back and incorporate existing drugs in a tailored manner, bringing us to the feet of an important leap in achieving these important medical goals, more so in a manner that is superior in feasibility and regulatory approval.

When reading about your innovative BEPO^TM polymeric technology, I contemplated using it in order to localize the effects of well-known therapeutic proteins, granting them an opportunity to display enhanced safety and efficacy profiles. The array of anti-TNFα therapeutics (three monoclonal anti-TNFα full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab’ fragment of anti-TNFα antibody certolizumab pegol, extracellular domain of TNFα receptor 2/IgG1-Fc fusion protein etanercept) are all biological agents that neutralize the effects of the pivotal pro-inflammatory cytokine, TNFα². The successful introduction of these drugs into different inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, psoriasis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis and Behçet’s disease, was followed by concerns regarding systemic adverse events (e.g., malignancy and infection)^3,4. Following the reports on celecoxib and anti-PSMA/CD3 being incorporated into BEPO^TM polymer for long-acting local injection^5,6, it is logical to suggest that the optimal candidates for the next development would be one of the anti-TNFα agents. Not only would such localized immunotherapy promote efficacy and safety, it would enable reaching out to new indications, such as spinal cord injury (SCI)⁷, kidney diseases or chronic wounds healing.

For addressing the complex issues with formulating relatively small biological drugs (anti-TNFα are in the range of 51-147kDa ) into a controlled-delivery system, while preserving the activity, the flexibility of the system is very important. I was impressed to learn that with your BEPO^TM technology different ratios of PLA:PEG can be investigated for the optimal formulation characteristics.

A further commercial point of interest for this project is strengthened due to several of the anti-TNFα agents being developed as biosimilars (Sandoz received marketing authorization for biosimilars Hyrimoz® adalimumab; Erelzi^®- etanercept and Zessly® infliximab).

Given the discussed unmet therapeutic needs, technological feasibility and additional commercial benefits, I recommend the anti-TNFα therapeutics as an ideal candidate for development into long-acting injectables using BEPO^TM polymeric technology.

LITERATURE

1. Lagassé, HA Daniel, et al. "Recent advances in (therapeutic protein) drug development." F1000Research6 (2017).
2. Mitoma, Hiroki, et al. "Molecular mechanisms of action of anti-TNF-α agents–Comparison among therapeutic TNF-α antagonists." Cytokine101 (2018): 56-63.
3. Ianculescu, Irina, and Michael H. Weisman. "Infection, malignancy, switching, biosimilars, antibody formation, drug survival and withdrawal, and dose reduction: what have we learned over the last year about tumor necrosis factor inhibitors in rheumatoid arthritis?." Current opinion in rheumatology3 (2016): 303-309.
4. Bongartz, Tim, et al. "Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials." Jama19 (2006): 2275-2285.
5. Hurtig, M., et al. "Intra-articular injection of a polymer/celecoxib formulation for long-term control of postoperative inflammation." Osteoarthritis and Cartilage24 (2016): S526-S527.
6. Leconet, Wilhem, et al. "Anti-PSMA/CD3 Bispecific Antibody Delivery And Anti-Tumor Activity Using A Polymeric Depot Formulation." Molecular cancer therapeutics(2018): molcanther-1138.
7. Esposito, Emanuela, and Salvatore Cuzzocrea. "Anti-TNF therapy in the injured spinal cord." Trends in pharmacological sciences2 (2011): 107-115.