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Medicine Pharmaceutics > mAbs recycling > Flashcards

mAbs recycling Flashcards

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

A

decreases

25
Q

______ clearance with a low pI

A

lower

26
Q

what must be done to ensure the quality of the mAbs

A

prevent charge/ pI variations

27
Q

what can the administration of therapeutic mAbs lead to?

A

formation of anti-drug antibodies (ADA)

28
Q

what do ADAs do to mAbs

therefore effects

A

bind to the mAb, form immune complexes impacting on PK, PD, safety and efficacy of mAbs.

29
Q

bad responses of ADAs

A

hypersensitivity: anaphylaxis

accelerated clearance

30
Q

TF: ADAs are neutralising

A

false

can be neutralising or non-neutralising

31
Q

drop of mAb concentration in blood could be due to?

A

ADAs

This drop is probably due to a higher clearance of immune complexes

32
Q

how to tackle decreased blood concentrations due to ADAs

A

might need to increase dose to achieve desired exposure. This drop is probably due to a higher clearance of immune complexes

33
Q

binding of mAb to FcRn and recycling contributes to?

A

half life

34
Q

mAbs PK is usually dependent on?

A

biology of target antigen

35
Q

PK dose proportionality of mAbs?

A

Non-linear PK at low doses

Linear PK at high doses after saturation of target

36
Q

mAbs distribution is usually limited too?

A

blood and interstitial space

37
Q

mAbs partitioning from blood to tissues is typically ____%

A

5-15%

38
Q

TF: there is no clearance of intact antibody

A

TRUE

39
Q

TF: immunogenicity in animals is predictive of immunogenicity in humans

A

FALSE

40
Q

Novel antibody formats?

A

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
Q

bispecific IgG is much more _____

A

unstable

42
Q

example of a antibody fragment?

A

take one part

e.g. single chain Fc region

43
Q

novel formats are ____ complex than mAbs

A

more

44
Q

in novel formats, different molecular domains can be linked through?
what does this mean?

A

flexible linkers- we pick and choose what we want in the structure and discard what we dont want

45
Q

for novel formats there is a _______ in stability

A

decrease

46
Q

for novel formats there is a _______ in solubility

A

decrease

47
Q

why is there decreased stability and solubility in novel formats of mAbs?

A

synthetic so can form aggregates

48
Q

aggregates are more likely to trigger?

A

an immune response

49
Q

novel formats tend to lose a lot of the?

A

dose

50
Q

what do fusion proteins consist of?

A

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
Q

the Fc portion in fusion proteins typically contain?

A

the hinge region usually along with the conserved N-glycosylation site in the CH2 domain

52
Q

in fusion proteins the half-life is ______

A

extended

53
Q

what is the most prominent antibody fragment?

A

FAB

54
Q

what drugs do Antibody drug conjugates (ADC) deliver?

A

mAb employed as drug delivery agents with chemotherapeutic drugs, immunotoxins, radioisotopes or cytokines

55
Q

how is the drug released from the antibody?

A

cleavable linker in either lys or cys residues allowing release

56
Q

ADCs can be either ____ specific or ______ specific

A

bi

multi

57
Q

what does bi or multi specific mean?

A

antibodies contain two or more variable domains with affinity for different antigen

58
Q

Bispecific formats comprise ….. based constructs

A

IgG like and FAB fragment based constructs

Medicine Pharmaceutics (6 decks)

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