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Medicine Pharmaceutics > mAbs recycling > Flashcards

mAbs recycling Flashcards

(58 cards)

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1
Q

what mediates recycling of albumin and IgG

A

neonatal Fc receptor

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2
Q

what is IgG?

A

antibodies

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3
Q

what happens when a antibody binds to the Fc receptors on cells?

A

IgG moves into one of t he endocytotic vesicles
the unbound IgG will be sorted for catabolic degradation to just the amino acids

those bound will get recycled and remade

pH raises to 7.4 and the binding stops and the IgG is released back into the blood

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4
Q

how does pH regulate Fc binding to the FcRn:

IgG binds at ______ pH

A

IgG binds at ACIDIC pH

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5
Q

what is the CQAs? example

A

critical quality attributes

FcRn binding affinity is a CQA defined by industry

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6
Q

what does industry want mAbs to do in relation to Fc receptors?

A

bind well but also be released when needed

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7
Q

how can we modify mAbs binding to FcRn?

A

modifying THE aa SEQUENCE

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8
Q

When the antigen is bound to the mAbs can it still be taken up by FcRns?

A

yes as the antigen is bound to the FAB region and the Fc region can bind to the FcRn at the same time

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9
Q

what can this dual binding to antigens and FcRn lead to in relation to antigens half life?
is this good or bad

A

extension of half life- we might not want this

need to find a way to release the antigen from the FAB during recycling

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10
Q

IgG types 1 and 2 and 4 have a half life of?

A

21 days

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11
Q

IgG type 3 has a half life of?

A

7 days

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12
Q

as you _____ the molecular mass you can have a very high half life

A

decrease

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13
Q

types of IgG’s?

A

natural and recombinant

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14
Q

TF: all IgGs are glycosylated

A

true

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15
Q

TF: glycosylation is required for an IgG antibody long half life

A

FALSE

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16
Q

what is the shorter half life of Fc fusion molecules in comparison to the whole IgG been attributed to?

A

the lower binding affinity to FcRn

the glycol mediated disposition and the receptor (of fusion partner) mediated disposition

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17
Q

fusion protein is a ______ ______ of a IgG. this means ______ is important

A

synthetic mimic

glycosylation

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18
Q

why is charge important on mAbs?

A

as often the surface of a cell is negatively charged and the receptors can also be negative

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19
Q

what is a powerful way of improving PK of mAbs relating to charge?

A

change the pI

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20
Q

what can cause charge variation of mAbs

A

manufacturing:
uncontrolled mutations
glycosylation

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21
Q

what is the normal pI of mAbs?

A

about 8

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22
Q

mAbs: with a pI of about 8 and at pH 8 you have a half life of about ______

A

20 days

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23
Q

as you increase the pI, why can recycling decrease?

A

the molecule will be constantly charged, meaning it doesn’t feel the changes in endocytotic vesicle so doesn’t bind to FcRn and doesn’t get recycled
Hence increasing the pI decreases the half life.

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24
Q

increasing the pI _______ the half life

25
______ clearance with a low pI
lower
26
what must be done to ensure the quality of the mAbs
prevent charge/ pI variations
27
what can the administration of therapeutic mAbs lead to?
formation of anti-drug antibodies (ADA)
28
what do ADAs do to mAbs | therefore effects
bind to the mAb, form immune complexes impacting on PK, PD, safety and efficacy of mAbs.
29
bad responses of ADAs
hypersensitivity: anaphylaxis | accelerated clearance
30
TF: ADAs are neutralising
false | can be neutralising or non-neutralising
31
drop of mAb concentration in blood could be due to?
ADAs | This drop is probably due to a higher clearance of immune complexes
32
how to tackle decreased blood concentrations due to ADAs
might need to increase dose to achieve desired exposure. This drop is probably due to a higher clearance of immune complexes
33
binding of mAb to FcRn and recycling contributes to?
half life
34
mAbs PK is usually dependent on?
biology of target antigen
35
PK dose proportionality of mAbs?
Non-linear PK at low doses | Linear PK at high doses after saturation of target
36
mAbs distribution is usually limited too?
blood and interstitial space
37
mAbs partitioning from blood to tissues is typically ____%
5-15%
38
TF: there is no clearance of intact antibody
TRUE
39
TF: immunogenicity in animals is predictive of immunogenicity in humans
FALSE
40
Novel antibody formats?
antibody fragments antibody drug conjugates bispecific: modified IgG to which a second part variable region has been attached so antibody will bind to 2 targets multi specific- antibody possessing multiple binding sites
41
bispecific IgG is much more _____
unstable
42
example of a antibody fragment?
take one part | e.g. single chain Fc region
43
novel formats are ____ complex than mAbs
more
44
in novel formats, different molecular domains can be linked through? what does this mean?
flexible linkers- we pick and choose what we want in the structure and discard what we dont want
45
for novel formats there is a _______ in stability
decrease
46
for novel formats there is a _______ in solubility
decrease
47
why is there decreased stability and solubility in novel formats of mAbs?
synthetic so can form aggregates
48
aggregates are more likely to trigger?
an immune response
49
novel formats tend to lose a lot of the?
dose
50
what do fusion proteins consist of?
a protein, peptide or receptor exodomain fused to the Fc region of the mAb Fc portion typically consists of the hinge region usually along with the conserved N-glycosylation site in the CH2 domain
51
the Fc portion in fusion proteins typically contain?
the hinge region usually along with the conserved N-glycosylation site in the CH2 domain
52
in fusion proteins the half-life is ______
extended
53
what is the most prominent antibody fragment?
FAB
54
what drugs do Antibody drug conjugates (ADC) deliver?
mAb employed as drug delivery agents with chemotherapeutic drugs, immunotoxins, radioisotopes or cytokines
55
how is the drug released from the antibody?
cleavable linker in either lys or cys residues allowing release
56
ADCs can be either ____ specific or ______ specific
bi | multi
57
what does bi or multi specific mean?
antibodies contain two or more variable domains with affinity for different antigen
58
Bispecific formats comprise ..... based constructs
IgG like and FAB fragment based constructs

Medicine Pharmaceutics (6 decks)

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