mAbs recycling - biologics 2 Flashcards
what is mAbs recycling?
- Neonatal Fc Receptor (FcRn) mediates recycling of albumin and IgG.
- So called Brambell receptor or FcRn.
- Fc region binds to FcRn
- IgG binds at at acidic pH (endosomal, pH 6), low affinity at pH 7-7.4.
- IgG taken p by monocytes or endothelial cells through endocytic mechanisms
- IgG not bound will be sorted to lysosomes for degradation
- FcRn binding affinity is one of the CQAs
- Fv region may also bind to FcRn and alter interactions
- Antibody and antigen complexes are also recycled through FcRn pathway
what is the glycosylation impact on mAbs PK?
- All IgGs (natural and recombinant) are glycosylated.
- Glycosylation is not required for an IgG antibody’s long half- life
- However for Fc fusion proteins, The shorter half-life of an Fc-fusion molecule in comparison to the whole IgG has been attributed to the lower binding affinity to FcRn, the glycan mediated disposition and the receptor (of fusion partner) mediated disposition
what os the charge and PI impaact on mAbs PK?
- Changing the pI of mAbs is powerful way to improve KP.
- Charges variation can arise from manufacturing processes
- Charges differences may impact on both PK and PD
what is the result of admin of therapeutic mAb?
may result in the formation of anti-drug antibody
what does a anti-drug antibody do?
binds to the mAb to form a complex which impacts on the PK and safety of the mAbs
what may happen during an ADA?
they may cause a hypersensitive response such as anaphlaxis and infusion reactions this may lead to acceleration of clearance of the drug
how do mAbs bind?
very specific for the target antigen
binding to FcRn and recycling contribute to its half lif
what is the PK/PD of a mAb?
PK is usually dependent on the biology of the target antigen
what is the dose proportion for a mAb?
non linear PK at low doses
linear PK at high doses after a saturation of the target
what is the distrubution of a mAb/
usually limited to blood and the interestial tissue
partionining from the blood to tissue is usually 5-15%
how are mAbs metabolised/
usually catabolims by proteolytic degradation to produce amino acids
how are mAbs excreted?
no renal clearance of the intact antibody
what is the immunogenecity of a mAb?
formatiomn of ADA against mAb could occur
- this would impact on the PK and PD of the mAb
the reaction of animals cannot be used to compare against humasn
what are the novel formats of mAbs?
- antibody fragments
- fusion protein
- antibody drug conjugates
- bispecific
- multispecific antibodies possessing multiple antigen binding sites
what are novel formats more complex then mabs?
- different antigen binding domain in the same molecule
- different molecular domains linked through flexible linkers
- heterogenous product throught the conjugation, synthesis, physical and chemical attributes
what are antibody fragments?
they skip the Fc part of the mAb
the most prominent type if the fragment antiboyd binding part
single domain antibodies - made flexible
what are fusion proteins?
major class of new products
comprise of a protein, peptide or receptors exodomain fused to the Fc region of the mAb.
the Fc portion typically contains hinger region
the half life is extended
what is a ADC?
mAb employed as drug delivery agent with chemotherapeutic drugs
cleavable link in either Lys or Cys residue allowing rhe release
what is a multifunctional antibody?
bispecific or multispecific antibodies contain two or more viable domains with specific affinity to bind to different antigens
what may cause aggregation of mAbs?
freezing or lyophilisation
what is recombinant human insulin engineering?
- monomer 51 aa little protein structure
- exists naturally as a hexameric structure of 6 inuslin monmers
- hexamer adopts a structure of a globular protein
- two axial ZNn ions with 6 histidine side chains
why do we use recombinant human insulin/
allows formulation to achieve fast acting and long acting insulin
how would you change grom a hexamer to be able to use it?
- conversion to dimeric and monomeric
- faster acting on sub-cut admin
- rapid absorption
- rapid response
why do we no use the insulin hexamer?
hexamer is not absorbed
only way to be absrorbed is as a dimer or a monomner.
you need to formulate it as a hexamer and then covert it
the faster acting you want the insulin - you need it to be a monomer
how do you produce fully human recombinant antibodies?
- the mouse IgG gene is replaced with human transgenes to produce a transgenic mouse with human DNA
- mouse immunised to raise its immune response
- B cell selection to produce human antibodies with desired specificity
- antiboyd effection function longer circulation
- if the antibody doesnt match it will be destroyed
what is the half life of fully human recombinant anitbodies?
14-21 days
what are the pharmacokinetics of mAbs?
where there are relatively large loading doses and an i/v route of admin there will high a very high peak conc and then it will reach a trough level which needs to be monitored before the next dose
what would happen if a patient had a reaction to the anti antibody drug?
if there not a flatline for the dosing of this then you would need to look into another antibody that would work.
if you are not already using a human antibody try and find one that is
what is the purpose of Fc fragment engineering?
Fc engineering maintains interaction with immune system and binding site for antibody recyling FcRn to enable long circulation times but may not uyet be as long in practice
what does a high Kd value mean?
this means it has a weak binding
what is the relationship between binding and elimination?
the weaker the binding (higher Kd) the faster they will be eliminated
