History of Biopharmaceuticals and Biologics

History of Biopharmaceuticals

• Biotechnology merges biology and technology for useful products from raw materials.
• Karl Ereky, a Hungarian engineer, coined the term in 1919.
• Genentech produced somatostatin in 1977, beginning the biotechnology age using recombinant DNA technology.
• Eli Lilly's human insulin (using recombinant DNA tech) was FDA-approved in 1982. This was the first human insulin produced via this method.

Biologics vs. Small Molecule Drugs

• Biologics are medications isolated from natural sources (human, animal, microbial) or made through biotechnology.
• Includes vaccines, blood components, gene therapy, tissue, recombinant proteins, and antibodies.
• Biologics are larger and more complex than small molecule drugs. Ex: Antibodies (~150 kilodaltons) vs. small molecules (~21 atoms).
• Biologics production often uses living cells/tissues, while small molecules use chemical synthesis. Ex: Insulin is a biologic (bacteria), metformin is a small molecule (chemical).
• Biologics and small molecule drugs have different FDA review/approval processes. Insulin, though initially a drug, is now regulated as a biologic.
• Generic biologics (like insulin) are possible due to FDA regulation, potentially lowering prices via competition.

The Rise of Biologics

• Biologic drug approvals have significantly increased.
• In 2023, biologics accounted for 48% of new drug approvals, exceeding small molecule drugs.
• This trend is driven by new biological modalities and the FDA's CBER (Center for Biologics Evaluation and Research).

Therapeutic Areas and Product Categories

• High biologic development in cancer, infectious diseases, autoimmune disorders, and neurological diseases.
• Key biologic product categories in development: monoclonal antibodies, vaccines, recombinant proteins, cell therapy, gene therapy.

Protein Structure

• Four levels of protein structure:
• Primary: linear sequence of amino acids.
• Secondary: repeating patterns (alpha-helices, beta-sheets).
• Tertiary: 3D folding of a single protein.
• Quaternary: arrangement of multiple protein subunits.

Factors Affecting Protein Structure and Function

• Tertiary structure is crucial for a protein's biological properties, determined by amino acid sequence, chain alignments, glycosylation, and cellular environment.
• Protein folding stabilized by: disulfide bonds, hydrophobic interactions, ionic interactions, hydrogen bonds.

Protein Conjugation and Glycosylation

• Protein conjugation attaches a prosthetic group (inorganic or organic) to a protein. Examples include metals (iron), lipids, and carbohydrates (glycosylation).
• Glycosylation adds sugar molecules (oligosaccharides) to proteins.
• Contributes to proteomic diversity.
• Types: N-linked (asparagine) and O-linked (serine/threonine).
• Glycosylation affects protein recognition, interaction, and solubility.
• Affects protein stability (thermal, aggregation, proteolysis).

Other Post-Translational Modifications

• Chemical modifications (e.g., carboxylation, hydroxylation, sulfation, amidation) also alter protein properties.
• Manufacturers can modify glycosylation to enhance stability and therapeutic benefits.

Protein Production

• Ex vivo protein production uses different expression systems (E. coli, yeast, mammalian, plants).
• The desired protein's DNA is inserted into the host cell.

Comparison of Expression Systems

• Host cell selection is critical in recombinant protein production.
• E. coli (bacterial): Simple, easy handling, rapid growth, high yield, but no glycosylation.
• Yeast: Simple growth, similar to mammalian cells, fast growth, good yield, and good glycosylation, but glycosylation may not be human-like.
• Mammalian cells: Best folding and human-like glycosylation, but slow culture and expensive production.
• Plant cells: Simpler growth than mammalian, but limited to plant-based products.

Antibody Production and Function

• Antibodies are therapeutic proteins naturally produced to fight foreign invaders.
• Antibody production in the body: Antigens bind to B cells with matching antibodies on their surface. This activates B cell multiplication & antibody secretion.
• Antibodies mark foreign molecules like viruses/bacteria for destruction. Macrophages ingest these marked invaders. Lymphocytes can attack infected cells.

Monoclonal Antibody Production

• Hybridoma technology produces monoclonal antibodies.
• Animal challenged with antigen.
• Spleen cells (containing B cells) fused with myeloma cells (unlimited proliferation).
• "Hybridoma" (fused) cells cultured, producing large quantities of antibodies.
• Antibodies harvested.

Types of Antibodies and Their Production

• Types: monoclonal, polyclonal, recombinant.
• Recombinant antibody production uses DNA sequencing & bacterial expression systems, cheaper/faster than hybridoma.
• Offers flexibility in antibody format & species.
• Advantages include lower cost, no animal use, flexible formats (e.g., Fab fragments).

Biologics Workflow and Manufacturing

• Biologics development is lengthy (12-15 years) & expensive.
• Steps: Target identification, assay construction & target screening, target validation, safety package development, clinical trials (phases 1-3), FDA review & approval.
• High cost due to biologics' complexity, low patient numbers for some, and extensive safety testing.

Monoclonal Antibody Manufacturing

• Target gene cloning into a vector.
• Vector insertion into a host cell.
• Cell culture and expansion.
• Large-scale bioreactor culture.
• Purification to isolate antibody.
• Quality control throughout.

Impurities in Recombinant Protein Production

• Potential contaminants: cell debris, viruses, protein contaminants, endotoxins.
• Purification methods are crucial for removing impurities and ensuring purity.

Factors Influencing Biologic Drug Cost and Safety

• Manufacturing complexity, host cell type (bacteria, yeast, mammalian) affect cost.
• Immunogenicity (immune system response to biologic) and toxicity are concerns. Mammalian cell expression systems are often preferred.
• Humanized/fully human antibodies have lower immunogenicity/toxicity.

mRNA-Based Antibody Therapy

• mRNA encodes the desired antibody.
• mRNA administered to the patient.
• Body cells express the antibody.
• Antibody targets/neutralizes intended targets (e.g., tumor cells, bacteria).
• Advantages: safety, reduced risk of long-term effects, personalized therapy.
• Challenges: higher production cost, expression difficulty, immune sensor activation.

mRNA-Based COVID-19 Vaccines

• mRNA vaccines carry the genetic code for the SARS-CoV-2 spike protein.
• Body cells express the protein, initiating an immune response.

Conclusion

• Biologics use in drug development is increasing.
• Production, manufacturing, cost, and safety considerations are important, to be further detailed in the next session (stability and therapeutic property development).

This quiz explores the history and development of biopharmaceuticals, highlighting significant milestones in biotechnology. It distinguishes between biologics and small molecule drugs, examining their differences in production and complexity. Perfect for those interested in the intersection of biology and medicine.