Biologics vs. Small Molecule Drugs: A Comparative Analysis

Welcome to the ultimate showdown of the biopharma world! Biologics- a group of large, complex molecules, derived from living organisms; and small molecules which are chemically synthesized compounds with low molecular weight. Drugs belonging to these two therapeutic classes comprise distinct characteristics, mechanisms of action, and therapeutic applications.

Biologic drugs, including but not limited to proteins, antibodies, and nucleic acids, are large molecules (>1kDa) produced using recombinant DNA technology (RDT) and are known for their specificity in targeting disease mechanisms. These are also administered via injections since they are unable to withstand the harsh gastrointestinal conditions. Examples include monoclonal antibodies (mABs) like trastuzumab for cancer and adalimumab for autoimmune diseases. On the other hand, small molecule drugs (0.1-1kDa) are orally administered with the ability to diffuse across cell membranes to reach intracellular targets. Classic examples of small-molecule drugs are aspirin, atorvastatin, and metformin.

The mechanisms of action for biologics and small-molecule drugs vary greatly. Biologics typically target the components of the immune system that directly or indirectly assist in fighting against diseases whereas, small-molecule drugs interact with enzymes, ion channels, or receptors, modulating biochemical pathways for therapeutic effects.?

Let’s look at trastuzumab: It is an antineoplastic mAB that targets and binds with the extracellular domain of human epidermal growth factor receptor 2 (HER2). This disallows the formation of HER2 homodimers blocking HER2-mediated signaling ultimately preventing cancer cell proliferation and growth.?It also further recruits immune cells to destroy HER2+ cancer cells.

Let’s look at aspirin:? Aspirin belongs to a class of small molecule therapeutic drugs called NSAIDs- non-steroid anti-inflammatory drugs. It blocks the functioning of the ubiquitously expressed cyclooxygenase enzyme which catalyses prostaglandin formation. Prostaglandin (lipids with hormone-like functions) are produced at sites of tissue damage or infection causing inflammation, swelling, pain, and fever.

Therapeutically, biologics have revolutionized treatment for chronic and complex diseases like autoimmune disorders, cancers, and genetic conditions. They enable significant advancements in personalized medicine, exemplified by biologics like infliximab and etanercept for rheumatoid arthritis. They are also reported to have fewer off-target interactions. Whereas, with broad applicability and established therapeutic profiles, small-molecule drugs remain essential for treating a wide range of acute and chronic conditions, including infections, cardiovascular diseases, and metabolic disorders. Due to their broader range of action, significant side effects like gastrointestinal bleeding and renal impairment have been reported with long-term use and large dosages.

Cost and accessibility highlight that biologics are often more expensive due to their complex production and development processes, limiting accessibility despite the emergence of biosimilars as more affordable alternatives. Biologics production involves living cell cultures and sophisticated biotechnological processes, requiring rigorous testing to ensure consistency and purity. Regulatory pathways are stringent due to their complexity and potential immunogenicity. Small molecule drugs, however, are easier and cheaper to produce, relying on chemical synthesis with a generally shorter and less costly development process. These are also widely available, with generic versions enhancing their accessibility.

In conclusion, biologics and small-molecule drugs each offer unique benefits and address different medical needs. Biologics excel in precision and targeted therapy, while small-molecule drugs remain crucial for their broad applicability and cost-effectiveness. Ongoing advancements in biotechnology and pharmacology promise to refine these therapies further, enhancing their efficacy, safety, and accessibility.

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References

1. Brennan, F. R., & Dolman, C. (2018). Biologics in medicine: an update. Trends in Pharmacological Sciences, 39(1), 25-29.

2. Leader, B., Baca, Q. J., & Golan, D. E. (2008). Protein therapeutics: a summary and pharmacological classification. Nature Reviews Drug Discovery, 7(1), 21-39.

3. Mellstedt, H. (2013). Biosimilars: Europe is ahead. The Lancet, 381(9881), 197-199.

4. DiMasi, J. A., Grabowski, H. G., & Hansen, R. W. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics, 47, 20-33.

5. Beck, A., Reichert, J. M., Therapeutic Fc-fusion proteins and peptides as successful alternatives to monoclonal antibodies, mAbs, 3:5, 415-416.

6. Mullard, A. (2020). 2020 FDA drug approvals. Nature Reviews Drug Discovery, 20(2), 85-90.

7. van der Neut Kolfschoten, M., et al. (2007). Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science, 317(5844), 1554-1557.

8. Walsh, G. (2014). Biopharmaceutical benchmarks 2014. Nature Biotechnology, 32(10), 992-1000.

9. Smolen, J. S., et al. (2016). A systematic review of international guidelines for the management of rheumatoid arthritis. Annals of the Rheumatic Diseases, 75(1), 70-80.

10. Pichler, W. J. (2006). Adverse side-effects to biological agents. Allergy, 61(8), 912-920.

11. Gutierrez C, Schiff R. (2011). HER2: biology, detection, and Clinical Implications. Archives of Pathology & Laboratory Medicine. 135(1):55–62.

12. Vane JR, Botting RM. (2003). The mechanism of action of aspirin. Thrombosis Research. 110(5-6):255–258.

Written by Ameya Parkar , Nanomedicine Research Group, ICTMumbai .

Edited by Vishakha Kurlawala , Science Communicator, Nanomedicine Research Group, ICTMumbai