Biologic drugs are a class of medicines derived from living organisms, like animal cells or bacteria. Unlike small-molecule drugs such as aspirin, which are made through chemical synthesis, biologics are exceptionally large and complex. For example, a common biologic like a monoclonal antibody can contain over 20,000 atoms, while a small-molecule drug may have only 20. This complexity allows biologics to perform highly specific functions.
Composed of proteins, nucleic acids, or entire cells, they can interact with disease processes in ways chemically synthesized drugs cannot. Their high specificity allows them to bind to distinct targets, making them effective for managing complex conditions like cancer, autoimmune disorders, and genetic conditions. The development of these intricate molecules follows a specialized path.
Target Identification and Validation
The first step in discovering a new biologic therapy is identifying a suitable target within the body. A target is a specific biological molecule, often a protein or a gene, that is associated with a disease. The goal is to find a component whose function can be modified by a drug to produce a therapeutic benefit.
To find these potential targets, scientists rely on advanced fields like genomics and proteomics. Genomics involves studying an organism’s genes, using techniques like genome-wide association studies (GWAS) to find genetic variations linked to a specific disease. Proteomics complements this by analyzing the set of proteins in a cell, comparing healthy and diseased states to see which proteins are dysregulated.
Once a potential target is identified, it must undergo validation. This phase confirms that the target has a direct role in the disease and is suitable for therapeutic intervention. Validation experiments might involve using tools like CRISPR gene editing or RNA interference to turn off the gene that produces the target protein in lab-grown cells. If disabling the target halts or reverses signs of the disease in these models, it provides strong evidence of its relevance.
Hit Generation and Screening
With a validated target, the focus shifts to finding a biologic molecule that can interact with it beneficially. This stage, known as hit generation, involves creating and sifting through immense libraries of potential drug candidates to find an initial “hit”—a molecule that shows the desired binding activity.
For monoclonal antibodies, two prominent technologies are phage display and hybridoma technology. Phage display involves inserting antibody genes into bacteriophages, which then “display” these antibodies on their surfaces. This creates a massive library that can be screened against the disease target. Hybridoma technology involves immunizing an animal with the target antigen and then fusing the antibody-producing B cells with immortal cancer cells to create hybridoma cells that continuously produce a single type of antibody.
For other biologics, such as gene and cell therapies, the approach is different. In gene therapy, scientists may design messenger RNA (mRNA) sequences that instruct the body’s cells to produce a therapeutic protein. In cell therapy, such as CAR-T therapy, a patient’s immune cells are genetically engineered to recognize and attack tumor cells before being infused back into the body.
These candidates are then put through a screening process. High-throughput screening uses automated systems to rapidly test thousands of molecules for their ability to bind to the target or elicit a specific biological response.
Lead Optimization and Characterization
After the screening process identifies initial hits, the next phase is to refine these candidates into “leads” with drug-like properties. An initial hit may bind to the target, but its characteristics are often not suitable for use in humans. Lead optimization is a process of molecular engineering designed to improve the molecule’s performance, safety, and stability.
A primary focus of this stage is enhancing the molecule’s affinity and specificity. Affinity refers to how tightly the biologic binds to its intended target, while specificity is its ability to ignore other molecules in the body. Using techniques like site-directed mutagenesis, scientists can make precise changes to the amino acid sequence of an antibody to strengthen its bond with the target.
Beyond binding properties, researchers also optimize for stability and efficacy. Biologics are complex proteins that can be fragile and may degrade quickly in the body, so scientists engineer the molecule to be more stable and have a longer half-life. For antibody-based drugs, this may involve Fc engineering, which modifies the “stem” of the antibody to fine-tune its interaction with the immune system.
Preclinical Development
Before a promising lead candidate can be tested in humans, it must undergo extensive preclinical development. This stage is designed to rigorously evaluate the biologic’s safety and behavior in biological systems. The data gathered here is compiled to support an Investigational New Drug (IND) application submitted to regulatory authorities, which is required to begin clinical trials.
The evaluation relies on both in vitro and in vivo testing. In vitro studies are conducted in controlled laboratory environments, such as on human cells, to assess the drug’s effects at a cellular level. In vivo studies are performed in living organisms, typically animal models, to understand how the drug behaves in a complex biological system and identify potential toxicity.
During these studies, scientists examine the drug’s pharmacokinetics and pharmacodynamics. Pharmacokinetics describes what the body does to the drug—how it is absorbed, distributed, metabolized, and excreted (ADME). Pharmacodynamics describes what the drug does to the body—its biological effects and mechanism of action. This stage also addresses formulation and manufacturing feasibility, ensuring the biologic can be produced consistently at a large scale.