Understanding large molecule drugs: Insights into the development and potential of biologic therapies

Examples of large molecule drugs

Insulin, discovered in1921, was one of the first large molecule drugs to be successfully developed and mass-produced, marking a milestone in the history of biologics. This breakthrough demonstrated the potential of biologics to address complex conditions that traditional small molecule drugs could not tackle alone.

By enabling the precise regulation of blood sugar in diabetic patients, insulin highlights the power of large molecule therapies to target and modulate intricate biological pathways, transforming what was once a fatal diagnosis into a manageable condition for millions. Some other well-known examples of large molecule drugs include:

• Monoclonal antibodies (mAbs): These lab-engineered proteins are designed to target specific antigens, such as those found on cancer cells or inflammatory molecules, to modulate immune responses. mAbs have become crucial in treating a variety of complex diseases, offering an unprecedented level of specificity.
• Recombinant proteins: This category includes therapeutic proteins like insulin (mentioned above) and erythropoietin, which are produced using recombinant DNA technology in living cells. These proteins replace or supplement naturally occurring proteins in the body, addressing conditions ranging from diabetes to anemia. 
• Enzyme replacement therapies (ERTs): ERTs provide missing or deficient enzymes to patients with metabolic disorders, such as Gaucher disease and Fabry disease. These large molecule therapies are tailored to address specific enzyme deficiencies and correct metabolic pathways, helping to alleviate disease symptoms.

Key characteristics of large molecule drugs

• Size and structure: Their molecular weights, often above 5,000 daltons, require delivery methods like injections or infusions, as they cannot easily penetrate cell membranes.
• Composition: Comprised mostly of sugars, proteins, or nucleic acids, large molecule drugs have complex structures that cannot be easily replicated via traditional methods.
• Synthesis: Biologics are created within living cells through intricate biotechnological and bioengineering processes, making their production complex and susceptible to variability.
• Mechanism of action: Large molecule drugs often impact entire biological pathways, indirectly treating the disease by downregulating or knocking out specific proteins.
• Administration: Due to their sensitivity and complexity, large molecule drugs are typically administered via injection or infusion, although research to enable oral delivery is ongoing.
• Stability: These drugs are highly sensitive to temperature fluctuations and contamination, often requiring cold and ultracold storage and special aseptic processing requirements.
• Immunogenicity: Large molecule drugs may trigger immune responses that could affect their safety and effectiveness; scientists are working to minimize these reactions.
• Metabolism and excretion: Large molecule drugs are broken down within cells and recycled, affecting their half-life and how frequently they must be administered.

Advantages of large molecule drugs

Large molecule drugs offer targeted and effective treatments for complex diseases by interacting directly with specific biological pathways. This approach enables them to address underlying mechanisms in conditions like cancer and autoimmune disorders, increasing a patient’s chance of remission. Many biologics also boost the body’s natural immune response, expanding treatment options for patients who previously had limited options available.

Challenges of large molecule drugs

Biologics face unique challenges in development, from variability in cell-based production to strict storage and transportation requirements. While these complexities can lengthen timelines and increase costs, they are essential for ensuring consistent product quality and safety.

Development and manufacturing challenges

Developing and manufacturing large molecule drugs presents considerable challenges for biologic drug developers, including the following considerations:

• Commercial production: Large molecule drugs are inherently complex, making their production at commercial scale particularly challenging.
• Advanced techniques: Biologics are produced in living cells, which requires advanced techniques and specialized equipment to ensure consistent quality.
• Natural variability: Biological systems are variable by nature, making reproducibility difficult and requiring strict process controls and quality assurance.
• Storage and stability: These drugs often require specific conditions, such as refrigeration during transportation, to maintain stability and prevent degradation.
• Immune reactions: The increased potential for immune responses adds complexity, requiring careful monitoring and testing to ensure patient safety. 

As stated, these factors can lengthen timelines and increase costs; bringing a new biologic to market can cost between $800 million and $2.6 billion—or more.

The future of large molecule drugs

As the biologics industry continues to advance, key trends are emerging that promise to shape its future, from innovations in development to new manufacturing approaches. Here are five influential trends driving the evolution of large molecule drugs:

• Personalized medicine: Biologics are advancing personalized medicine, providing treatments tailored to patients based on their unique genetic profiles. 
• Biosimilar popularity: As patents on biologics expire, biosimilars are gaining popularity, offering more affordable and accessible options to patients in need. 
• Artificial intelligence: AI is set to revolutionize drug discovery and development by accelerating research and enhancing the precision of molecule engineering. 
• Continuous manufacturing: This method will optimize the production of large molecule drugs, lowering costs and ensuring a steady supply to meet demand.
• Advanced delivery systems: Advanced delivery systems enable precise targeting of specific tissues or cells, reducing side effects and improving outcomes.

How CDMOs can support large molecule drug developers

Contract development and manufacturing organizations (CDMOs) play a key role in supporting large molecule drug developers throughout the drug development journey. They offer specialized expertise and resources across the product lifecycle, providing key services such as cell line development, upstream and downstream process development, preclinical to commercial scale-up, and cGMP-compliant manufacturing, all of which are essential for biologics development.

By partnering with an experienced CDMO like Thermo Fisher Scientific, drug developers gain access to automated, high-throughput technologies, state-of-the-art facilities, and industry-leading expertise tailored to the unique needs of their drugs. This collaboration allows biotech and biopharma companies to bypass complex challenges and pitfalls and focus on innovation—with the peace of mind that their products meet the rigorous standards for patient safety and efficacy.