Biologics A Flashcards
Importance of Biologics:
- Biologicals revolutionised treatment for some life-threatening and rare disease i.e. diabetes, rheumatoid arthritis etc
- Their complexity, size makes them far more difficult to manufacture than small molecule medicines.
- 37% of the drugs market is biologicals.
- Blockbusters – pass billion dollar sales
- Strongest growth for companies
- Faster to have a biological on the market than a small molecule – due to how they are produced and tested
- Traditional chemical agonist/antagonist and the “one drug suits all” blockbuster are mature with higher failure rates in discovery pipelines, drug development, clinical trials and post-marketing approval.
- Drug discovery technologies to sustain paradigm yet to return on investment
- Biologicals developed by biotech companies (small) filing gaps of large pharma companies
- Replace diseased tissue functionality (e.g. protein hormones and blood factors, gene therapy and tissue engineering
- Highly specific binding to modify or block function to target
Biologics vs small molecule
- Versatility: replaced diseased tissue as weill as modify
- Unspecific binding to molecular structures other than molecular target can cause toxicity: not applicable with therapeutic proteins
- Blood levels of drug and duration of action in man not appropriate (e.g. elimination half life too long)/too short; critical metabolite spectrum) – not applicable to mAbs which have half life of about 3 weeks
- Less frequent dosing – long circulation times compared to small molecules drugs (week vs hours)
- Different structures for each indication – not applicable to the similarly structured monoclonal antibodies
- Inappropriate molecular target applies to both
- Immunogenic effects – higher risk for therapeutic proteins, addressed by Humanisation of proteins.
Different types of biologics on market:
- Peptides – were the first on the market – used as last line antibiotics
- Protein fragments
- mAbs,
- ADCs – antibody drug conjugates – means you have mab to which you have a cytotoxic drug attached which are conveyed into the cell, used mainly for cancer
- Viruses
- Vaccines
- New modalities such as LNP – lipid nano particles
Most mabs are?
- IgG
- Larger particle = more complex to formulate
Production (bioprocess)/ development.
- Immunization –= mice are immunised via injection = antigen production
- Prep of myeloma cells – cells which once fused with spleen cells can result in hybridoma capable of unlimited growth
- Fusion = hybridoma in presence of PEG – polyethlene glycol which causes the cell membrane to fuse. PEG attracts water molecules which causes the cell membrane to break
- Clone screening and picking – clones are screened and selected on basis of antigen specificity and immunoglobulin class
- Functional characterisation – using techniques such as LISA – identify colony with most productivity
- Scale up and wean – scale up clones producing desired antibodies
- Expansion – expand clones using bioreactors
Steps in production:
- Cell culture harvest
- Protein A chromatography
- Viral inactivation
- Polishing steps
- Viral filtration
- UF/DF
•Globalised manufacturing, produce in multiple sites smaller scale, increase titre, continuous manufacturing and productivity, change of cell types, move to no cells.
- Huge number of steps which slows down the production
Human antibody development?
- Started with mouse as creating Hu hybridomas was difficult (1975)
- Immunogenic reactions and rapid clearance
- Due to lack of Fc effector functions – recognised as foregin body and not recycled
- Move to recombinant engineering over last 2 decades:
- Chimeric – mouse variable region (Fv, antigen binding) (green)
- Humanised - mouse antigen binding loops (CDRs)
- Fully human antibodies produced via mouse.
How do mAbs work?
- CDC Antibody will bind to the surface and complement molecules that are attached to it = cytotoxicity
- Conjugates – antibody attached to the antigen = cytotoxicity
- Apoptosis induction = cell kills itself
- Ligand – cell cell blocking, receptor site blocked by antibody, ligand can therefore not bind and not penetrate cell.
- ADCC = antibody binds to specific antigen on surface = neutrophils that will attach to the antibody and induce cytotoxicity
Pharmacokinetics (PK) / Pharmacodynamics (PD)
mAb features contributing to PK
- Bottom = FC region (made of CH2 and CH3 fragments)– this induces the recycling of IgG which is the reason for the long half life.
- Glycan receptor = sugar. Gives chain off Fc region need to control this to ensure glycan mediated clearance and tissue distribution is adequate
- Antigen = target mediated disposition – effected by the charge of molecule which can lead to off target binding
Absorption of mAbs:
▫ Administration either i.v., SC or IM (patient usually injects themselves) injections
▫ Absorption for SC is variable (20-95%) facilitated by lymph system
▫ Rate of absorption is slow (maximal plasma concentration between 1-8 days following SC or IM injection
Elimination of mAbs:
▫ Not clearly understood
▫ Eliminated by proteolytic catabolism by lysosomal degradation. Means that your antibody that enters the cells cannot evade the endosome?? – results in recycled antibiotics
▫ Other mechanisms include target mediated clearance, non-specific pinocytosis (kind of endocytosis), Fc gamma receptor (FcR) mediated clearance.
▫ target-mediated elimination pathway involves interaction between a mAb and its pharmacological target (antigen), and represents the primary route of antibody clearance. The resulting immune complexes are then cleared from the body through reticulo-endothelial system (RES).
Pharmacodynamics of mAbs:
- PD refers to pharmacological effects elicited by a drug in the body.
- Differs from small drugs.
- PK/PD relationship of mAbs are unique due to mAB PK which are markedly influenced by the biology of the target antigen (TMDD)
