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Biotherapeutics > Monoclonal Antibody > Flashcards

Monoclonal Antibody Flashcards

1
Q

How many chains make up Ig?

A

4

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2
Q

What does the immunoglobulin fold result in?

A

strongest structure in protein biology

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3
Q

What does IgG have?

A

Sugar that is glycosylated making it a glycoprotein

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4
Q

What is long-term immunity down to>

A

Antibody production & secretion

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5
Q

What type of response occurs due to infection?

A

Polyclonal response

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6
Q

What is the polyclonal response?

A

Antigen cross-linking by multiple antibodies

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7
Q

Can you mimic the polyclonal response and why?

A

No - we need to find one monoclonal antibody that recognizes one epitope

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8
Q

For clinical treatment what do we need the monoclonal antibody to be?

A

Specific
High binding affinity for target

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9
Q

What is the immunoglobulin structure?

A

Tetrameric - 4 peptide chains joined by disulfide bonds

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10
Q

What region of the Ab is the antigen binding site?

A

Fab

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11
Q

What section is critical for pharmacokinetics?

A

Fc - trunk

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12
Q

What are characteristics of the finger part of the Ab?

A

hyper variable - short gene segments any combination of aa
Binds antigens

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13
Q

Define clinical pharmacokinetics?

A

Application of pharmacokinetic principles to the safe & effective therapeutic management of drugs in an individual patient

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14
Q

What part of the antibody is the PK profile relevant to?

A

Fc portion

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15
Q

What are 4 desirable characteristics of antibody drugs?

A

Good stability & solubility
long persistence
high selectivity & specificity
low risk for bioconversion to toxic metabolites

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16
Q

What is half life?

A

Time taken for serum conc. of drug to decrease by half its steady state conc

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17
Q

What is difference between selectivity & specificty?

A

Selectivity - breast cancer tissue
specificity - receptor on breast cancer cell

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18
Q

What does CDR stand for?

A

complementary determining regions

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19
Q

What is a paratope?

A

sequences of Ab making contact with antigen?

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20
Q

What is the epitope?

A

Sequence of antigen making contact with Ab

21
Q

What is the CDR responsible for?

A

Aa in CDR have right chemistry & folded in right way for interface for epitope & paratope bonding

22
Q

What is the half-life of Abs down to?

A

Salvage from lysosomal pathway by FcRn

23
Q

What is the MoA of salvaging Ab?

A

Fc gamma receptor binds to Fc portion ->
Internalized in early endosome -> pH in endosome drops ->
Antibody stops recognizing each other -> new receptor takes over (FcRn) -> rescues Ab ->
Returns to surface and is let go

24
Q

What gives pH control in IgG and FcRn recognition?

A

Glycoprotein

25
Q

What are 4 downfalls of IgG?

A

Not orally available
incomplete absorption following IM or SC admin
nonlinear distribution/elimination
leads to endogenous antibody response - alter efficacy

26
Q

Who were the first to produce the first murine mAbs from hybridomas?

A

Kohler & Milstein

27
Q

What were 4 downfalls of murine mAbs?

A

Allergic reaction
induction of anti-drug antibodies
short half life
poor recruiters of effector function ADCC & CDC

28
Q

What is muromonab-CD3?

A

immunosuppressant drug reducing acute rejection in organ transplants

29
Q

What does muromonab-CD£ target?

A

CD3 receptor on T cells

30
Q

What was developed to overcome downfalls of murine Ab?

A

Chimeric mouse-human antibodies were developed (ximab)

31
Q

How was ximab made?

A

grafting antigen-specific variable domain of mouse (35%) onto constant domains of human Ab (65%)

32
Q

What was the final engineered mAb?

A

humanized (zumab) developed

33
Q

What is the zumab?

A

Murine hypervariable regions (CDR) onto human Ab framework (95% human)

34
Q

What four thing does targeted cancer therapies do?

A

interferer with cell growth signaling or tumors blood vessel development
promote cancer cell death
stimulate immune system to destroy specific cancer cells
deliver toxic drugs

35
Q

What are 4 targets for cancer biology?

A

VEGF
EGFR
CD19
immune checkpoints

36
Q

What is HER2?

A

receptor tyrosine kinase essential for cell division & proliferation eg. Cardiac myocytes

37
Q

What are tyrosine kinase domains activated by?

A

Homodimerization & heterodimerization generally induced by ligand binding

38
Q

What happens when receptor overexpression or mutation occurs?

A

Induce dimerization - promote cellular proliferation & survival

39
Q

What does HER2 signalling promote cell growth through?

A

RAS-MAPK pathway

40
Q

What does HER2 signalling inhibit cell death through?

A

PIK3 AKT (target of mTOR) inhibits apoptosis

41
Q

What does trastuzumab target?

A

juxtamembrane (epitope) portion of EC domain of HER2 receptor -> prevents tyrosine kinase activation

42
Q

What doe preclinical models of Trastuzumab suggest?

A

recruits immune effector cells responsible for antibody-dependent cytotoxicity

43
Q

What is the loading dose of trastuzumab?

A

8mg per kg given IV

44
Q

What is a side effect of trastuzumab?

A

5% had cardiotoxic effects

45
Q

Why are people primarily resistant to trastuzumab?

A

Breaking of EC domain leaving P95 has already occurred - patients have already lost EC before treatment - epitope is gone

46
Q

What % of patients develop secondary resistance to Trastuzumab?

A

70%

47
Q

Which 2 proteins play are role in primary/acquire resistance to trastuzumb?

A

PTEN
Src

48
Q
A

Biotherapeutics (3 decks)

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