Lecture 13 - biologics Flashcards
what is the definition of a biological ?
A biological medicine is a medicine that is derived from a biological (living) source, such as bacteria or viruses, blood, tissues, or living cells in culture. Examples are vaccines, insulin, monoclonal antibodies, blood coagulation factor and recombinant DNA proteins
what is a monoclonal antibody definition?
Monoclonal antibodies are immunoglobulins (Ig) with a defined specificity derived from a monoclonal cell line. Their biological activities are characterised by a specific binding characteristic to a ligand (commonly known as antigen), and may be dependent on immune effector function such as antibody dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).”
what are the 5 different types of antibodies based on heavy chain and light chain ?
IgA (α),
IgD (δ),
IgE (ε),
IgG (γ),
IgM (μ)
what are IgG post-translational modification and glycosylation
Post-translational modifications (PTMs) are important quality characteristics that can impact drug stability, safety and efficacy.
- Serum half life, immunogenicity, PK characteristics of the mAb
PTMs occur during mAb production, purification and following administration.
Most common glycosylation and sites of glycosylation (mannose, Fucose, NAG, galactose)
Glycans play an important role in the immunity and recognition, therefore glycosylation must be controlled
how do mAbs exert their biological effects?
blocking
signallign
targeting
complement dependant cytotoxicity cdc
adcc - antibody dependant cell mediated cytotoxicity
what are clinical indications for anti-CD20 chimeric monoclonal antibody ?
non-Hodgkin’s lymphoma
chronic lymphocytic leukemia
rheumatoid arthritis
idiopathic thrombocytopenic purpura
pemphigus vulgaris
myasthenia gravisbb
what are physical drivers of mAb instability?
Can occur during any stage of product lifecycle.
During processing
Shear stress, Agitation, high pressure
During storage
Freeze-thaw, heat, light, extractables and leachables
During shipping, handling or in-use
Agitation, freeze-thaw, heat
discusses the physical instability of monoclonal antibodies
Sequence-dependent
For example, low or high isoelectric points (PI) in the CDR or Aggregation-prone regions. isoelectric point is the pH at which a molecule carries no net electrical charge
product-dependant factors; Antibody concentration
Formulation excipients
Packaging (Extractables & Leachables)
Microbiological
Denaturation
Loss of higher order structure through unfolding
Protein Aggregation
- Where self-associate and polymerize into aggregates or organized fibrils.
Native vs non-native aggregates
Covalent vs non-covalent aggregates
Soluble aggregates (nanometers) to insoluble aggregates ((sub)-microns)
why does mAb aggregation matter?
Reduced efficacy
Increases immunogenicity (e.g. neutralizing antibodies)
Increased risk of anaphylaxis and allergic reactions
Increased risk of injection site reactions e.g. phlebitis
what are types of therapeutic mAbs?
murine - muromomab
chimeric - abciximab
humanised - daclizumab
human - adalimumab
what are types of antibody therapy ?
monoclonal antibodies
next generation: antibody drug conjugates, improved delivery strategies, glyco-engineered antibodies, antibody fragments and bispecifics
