Podcast
Questions and Answers
Which type of cell expression system is noted for producing the most compatible products for humans?
Which type of cell expression system is noted for producing the most compatible products for humans?
What is considered a major advantage of mRNA-based antibody therapy over traditional recombinant protein therapies?
What is considered a major advantage of mRNA-based antibody therapy over traditional recombinant protein therapies?
Which statement about fully human antibodies is correct?
Which statement about fully human antibodies is correct?
What is a challenge associated with mRNA-based therapies?
What is a challenge associated with mRNA-based therapies?
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What is a potential outcome of administering mRNA encoding an antibody to a patient?
What is a potential outcome of administering mRNA encoding an antibody to a patient?
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What was the significance of Genentech's production of somatostatin in 1977?
What was the significance of Genentech's production of somatostatin in 1977?
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Which of the following is not a characteristic of biologics compared to small molecule drugs?
Which of the following is not a characteristic of biologics compared to small molecule drugs?
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What therapeutic area has seen a high number of biologics in development?
What therapeutic area has seen a high number of biologics in development?
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How has the FDA's decision altered the regulation landscape for insulin?
How has the FDA's decision altered the regulation landscape for insulin?
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Which one of the following best describes the primary structure of a protein?
Which one of the following best describes the primary structure of a protein?
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Why are biologics gaining a larger share of drug approvals?
Why are biologics gaining a larger share of drug approvals?
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Which category of biologics is not commonly mentioned in development?
Which category of biologics is not commonly mentioned in development?
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Which structural level of protein is characterized by the three-dimensional folding of a single protein molecule?
Which structural level of protein is characterized by the three-dimensional folding of a single protein molecule?
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What type of post-translational modification can alter protein properties by adding a sugar molecule?
What type of post-translational modification can alter protein properties by adding a sugar molecule?
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Which expression system is most beneficial for producing proteins with glycosylation similar to human proteins?
Which expression system is most beneficial for producing proteins with glycosylation similar to human proteins?
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What stabilizing interaction in protein folding is formed between cysteine residues?
What stabilizing interaction in protein folding is formed between cysteine residues?
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Which step in monoclonal antibody production involves fusing B cells with tumor cells?
Which step in monoclonal antibody production involves fusing B cells with tumor cells?
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Which characteristic is a disadvantage of using E.coli for recombinant protein production?
Which characteristic is a disadvantage of using E.coli for recombinant protein production?
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What is a common advantage of recombinant antibodies compared to traditional monoclonal antibodies?
What is a common advantage of recombinant antibodies compared to traditional monoclonal antibodies?
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What can significantly influence the stability of proteins as a post-translational modification?
What can significantly influence the stability of proteins as a post-translational modification?
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Which of the following is NOT a factor that contributes to the high production cost of biologics?
Which of the following is NOT a factor that contributes to the high production cost of biologics?
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What is the main role of glycosylation in protein function?
What is the main role of glycosylation in protein function?
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Study Notes
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).
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Description
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.
