Authors: Valentina Fiori, Tomas di Mambro

Modern medicine has witnessed a profound trasformation with the emergence of biological drugs. These sophisticated therapeutic agents, unlike traditional chemically synthesized molecules, represent a paradigm shift in disease treatment.

By precisely targeting the fundamental causes of illness through biological mechanisms, they offer unprecedented potential in managing chronic and severe conditions such as diabetes, autoimmune disorders, and cancer. Often described as “magic bullets”, biological drugs exhibit remarkable specificity, interacting with precise molecular targets.

This move towards “targeted therapies” involves selectively engaging cellular receptors, abnormal proteins, or disrupted signaling pathways, thereby modifying the disease’s progression at its core and propelling us towards personalized medicine.

Defining Biological Drugs: A Distinct Therapeutic Class

Several key distinctions set Biological Drugs apart from traditional chemically synthesized drugs:

  • Origin and Production: Biologics are derived from living organisms or complex biotechnological techniques like genetic engineering, contrasting with conventional drugs synthesized through controlled chemical reactions.
  • Size and Structural Complexity: Biologics are typically large macromolecules, such as proteins or nucleic acids, with high molecular weights and intricate three-dimensional structures. In contrast, chemical drugs are small molecules with well-defined and reproducible structures.
  • Stability: Biologics are generally less stable and require stringent storage conditions.
  • Immunogenicity: Their biological nature can also trigger an immune response (immunogenicity), leading to the formation of anti-drug antibodies.
  • Characterization: Due to their inherent complexity, complete characterization of biologics poses significant challenges, whereas chemical drugs can typically be exhaustively characterized.
  • Specificity of Action: Biologics exhibit very high action specificity, interacting with precisely defined molecular targets, which often translates to greater efficacy and more targeted side effects.

A fundamental principle governing biological drug development is “the process is the product.” This highlights that the final molecular structure, biological activity, efficacy, and safety of a biologic are intrinsically linked to its production process.

Even minor manufacturing variations can have significant consequences on the final product. Consequently, regulatory authorities approve not only the molecule itself but the entire production process to ensure consistency and quality.

The Intricate Journey of Biological Drug Development:

The development of biological drugs is a protracted, complex, and hightly regulated process that differs significantly from the development pathway for chemically synthesized drugs. Given their intricate nature and production involving living organisms, the principle of “the process is the product” is paramount, influencing every stage from initial research to post-market surveillance. While preclinical and clinical development phases are similar to traditional chemically synthesized drugs the initial discovery of a biologic drugs is different in various aspects

Research and Discovery

This foundational phase centers on identifying a pharmacological target – a specific receptor, an abnormal protein, or a disrupted signaling pathway implicated in a particular disease:

  • Target Identification: Genomics, proteomics, and bioinformatics tools play a crucial role in identifying molecules or biological pathways involved in disease pathogenesis. For instance, specific genetic mutations associated with severe conditions or proteins overexpressed in cancer cells might be identified. Access to extensive genetic databases and collaborations with academic and research institutions are critical.
  • Hit Identification: Once a target is identified, researchers seek biological molecules (such as antibodies or proteins) that can interact with it. Advanced technologies like High-Throughput Screening (HTS) and antibody libraries enable the screening of vast numbers of molecules to identify those exhibiting the desired activity against the target.
  • Lead Optimization: The initial “hit” compounds are then refined to enhance their desirable properties, including target affinity, specificity, stability, solubility, and reduced immunogenicity. This optimization process often involves sophisticated molecular engineering techniques.
  • Drug Candidate Selection: From the pool of optimized candidates, the molecule demonstrating the most promising efficacy and safety profile is selected to advance to the subsequent stages of development.

Preclinical Development

Conducted using both in vitro and in vivo models this phase assesses the drug candidate’s efficacy, safety, and pharmacokinetics before human trials.

  • In vitro Studies: involve experiments conducted on cells, tissues, or other biological components outside of a living organism, to evaluate the drug’s biological activity at the cellular and molecular level, as well as its potential toxicity.
  • In vivo Studies (Animal Models): Animal models (e.g., mice, rats) are used to mimic human disease characteristics. These studies are crucial for:
    • Pharmacodynamics (PD): Evaluating the drug’s effects on the body and its mechanism of action.
    • Pharmacokinetics (PK): Studying how the drug is absorbed, distributed, metabolized, and eliminated by the body. This is fundamental for determining dosing and frequency of administration.
    • Toxicology: Assessing the drug’s safety at single and repeated doses, identifying any target organs for toxicity. This includes studies on acute, sub-chronic, and chronic toxicity, genotoxicity (whether the drug can cause genetic mutations), and carcinogenicity.
  • Production of Material for Clinical Studies: During this phase, the biological drug’s production process must be scaled up to a pilot level, ensuring the active substance is produced according to Good Manufacturing Practice (GMP) guidelines to ensure purity and quality. This is a key aspect for biologics, where process variability can affect the final product’s structure and activity.
  • Communication with Regulatory Authorities: Before human studies begin, a submission for clinical trial authorization (Investigational New Drug – IND in the US, or Clinical Trial Application – CTA in Europe) is filed with regulatory authorities (e.g., EMA in Europe, FDA in the US), including all preclinical data.

Clinical Development (Human Trials)

This is the longest and most expensive phase of drug development, potentially lasting over 10 years and involving an increasing number of participants across several stages. This phase is common to traditional chemically synthesized drugs and involves VI phases

  • Phase I:

Objective: To assess the drug’s safety and tolerability in humans, determine its pharmacokinetic profile, and identify initial side effects.

  • Phase II:

Objective: To investigate the drug’s therapeutic activity (efficacy) in patients with the target disease and establish the optimal dosage.

  • Phase III:

Objective: To confirm the drug’s efficacy and safety in a large patient population, comparing it to standard treatments or a placebo. To evaluate the benefit-risk ratio on a large scale.

Participants: Involves hundreds or thousands of patients, selected to be as similar as possible to those who will use the drug in clinical practice.

  • Phase IV (Post-Marketing Surveillance):

After approval and commercialization, the drug continues to be monitored. This phase is crucial for detecting rare or late-onset adverse events that might not have been identified in previous phases due to the limited number of patients; studying the drug’s effects in specific patient subgroups (e.g., children, elderly, pregnant women); verifying long-term efficacy and exploring new therapeutic indications.

Technological  Driving Progress

Several key technological advancements are revolutionizing the discovery and development of biological drugs:

  • Protein and Antibody Engineering: The development of bispecific antibodies, antibody-drug conjugates (ADCs), antibody fragments, and other structural modifications enhances efficacy and reduces potential toxicity.
  • Gene therapy: advancements in delivery systems, gene editing tools, and therapeutic approaches, leading to new treatments for genetic disorders and cancers. These include the development of CRISPR-Cas9, which allows precise gene editing, and the use of nanoparticles and engineered viruses for gene delivery
  • RNA Technologies: The ability to manipulate RNA has revolutionized vaccine development, exemplified by mRNA vaccines.
  • Artificial Intelligence (AI) and Machine Learning: AI and machine learning are increasingly being applied to accelerate various aspects of drug discovery and development, including the identification of novel therapeutic targets, the design of new molecules, and the analysis of large and complex clinical datasets to predict outcomes and optimize treatment strategies.

The continuous evolution of these technologies promises to further accelerate the discovery and development of innovative biological drugs, offering hope for patients suffering from a wide range of debilitating diseases.

 

Valentina Fiori holds a PhD in Biochemical and Pharmacological Sciences, and is Biologics R&D Manager at Diatheva, where she leads the development of therapeutic recombinant monoclonal antibodies targeting oncology and infectious diseases. She combines scientific strategy with industrial collaboration, managing complex R&D programs that bridge academic innovation and biopharmaceutical application.

Tomas Di Mambro holds a PhD in Biochemical and Pharmacological Methodologies and is a Biologics R&D Specialist at Diatheva. With his expertise in recombinant antibody engineering and molecular biotechnologies, he contributes to the design, development, and optimization of innovative biologics for research and diagnostic applications.