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Immunology Exam 3 > ADAPTIVE IMMUNE RESPONSE TO BIOTHERAPEUTICS > Flashcards

ADAPTIVE IMMUNE RESPONSE TO BIOTHERAPEUTICS Flashcards

(80 cards)

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1
Q

WHAT IS IMMUNOGENICITY?

A

HOST IMMUNE RESPONSE AGAINST A THERAPEUTIC PROTEIN / Host immune system recognizes the drug as ‘non-self’

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2
Q

WHERE IS IMMUNOGENICITY STUDIED IN?

A

FORMATION OF ANTI-DRUG ANTIBODIES (ADA)

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3
Q

WHERE IS IMMUNOGENICITY LOCATED ON FDA A APPROVED LABEL?

A

ADVERSE REACTIONS

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4
Q

What is the variability of immunogenicity?

A

Highly variable

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5
Q

Immunogenicity incidence ranges from __% to nearly __% of subjects

A

0, 50

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6
Q

(T/F) Immunogenicity is extremely difficult to predict and mitigate

A

True

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7
Q

Data is usually stratified by ___ status to allow easy identification of the impact of immunogenicity

A

ADA

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8
Q

ADA does what to both efficacy and safety?

A

It reduces them

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9
Q

ADA reduce both efficacy and safety through which mechanisms?

A

Neutralizing drug activity, accelerating drug elimination and formation of immune complexes

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10
Q

Types of anti-drug antibodies (ADA)

A

Binding (non NAb) and Neutralizing (NAb)

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11
Q

What happens in the binding class of ADA?

A

Non-NAb interacts with the drug molecule but does not inhibit its binding to the pharmacologic target.

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12
Q

Where is the non- NAb located?

A

It is away from the active site

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13
Q

What happens in the neutralizing class of ADA?

A

NAb directly blocks interaction of drug with its pharmacologic target

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14
Q

Where is the NAb located?

A

It is located at the active site

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15
Q

Binding has an impact on

A

pharmacokinetics and safety

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16
Q

Impact of Neutralizing

A

Loss of efficacy/ impact on pharmacokinetics and safety

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17
Q

Both binding and neutralizing can be categorized as ____

A

clearing

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18
Q

clearing ADA are detected based on their what?

A

effects on pharmacokinetics

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19
Q

Non clearing ADA is also referred as

A

sustaining ADA

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20
Q

What happens when there’s a development of ADA?

A

Rapid decrease in plasma drug concentration

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21
Q

What happens when there’s multiple dosing of ADA?

A

Decrease in plasma concentration

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22
Q

Factors that influence Immunogenicity

A

biologic molecule, biologic product, antigen, and patient

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23
Q

biologic molecule

A
  1. sequence (rodent vs human sequence)
  2. allotype
  3. structure
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24
Q

biologic product

A
  1. formulation
  2. dose
  3. route of administration
  4. frequency of administration
  5. aggregates and impurities
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25
patient related factors
disease type disease activity concomitant therapies genetics
26
antigen
cell bound or soluble
27
Immunogenicity is largely thought to be a __-cell dependent phenomenon
T
28
Presentation to ____ cells leads to ADA generation
T helper
29
Presentation to ___cells limits ADA generation
Treg
30
___ and ____are thought to drive whether an immunogenic response occurs
Tepitopes, Tregitopes
31
___ the human content of the primary (amino acid) sequence decreases immunogenicity
increasing
32
Which antibody is the most immunogenic?
mouse or murine
33
Which antibody is the least immunogenic?
human/humanized
34
which antibody is moderately immunogenic?
chimeric
35
T/F rank antibody from most immunogenic to least immunogenic
Mouse (murine) > Chimeric > Humanized > Human
36
Muromanab
mouse antibody
37
Rituximab
chimeric antibody
38
trastuzumab
humanized antibody
39
adalimumab
human antibody
40
____ IgG sequences are more readily recognized as ‘non-self’ by the immune system
Non-human
41
How are Monoclonal antibodies (mABs) developed now?
humanized or fully human
42
mAbs with mouse Fc are eliminated ___ rapidly and need ____ frequent dosing
more, more
43
Which route of administration is more immunogenic than intravenous dosing?
Subcutaneous & Intramuscular injections
44
Subcutaneous & Intramuscular injections puts the drugs near antigen-presenting cells, __________
dendritic cells
45
Proteins must travel through ________ to reach the systemic circulation following SC/IM dosing
lymph nodes
46
Injections may lead to ____ inflammation, which further primes the immune system for response
local
47
T/F anti-inflammatory drugs, such as low-dose methotrexate, have been shown to reduce the development of anti-drug antibodies in patients.
True
48
True or False: The presentation of therapeutic proteins to t-helper cells is more likely to lead to the generation of anti-drug antibodies (ADA).
True
49
(T/F) In combination with adalimumab (Humira, anti-TNF), methotrexate reduces ADA incidence in a dose-dependent manner and increases serum adalimumab concentrations
True
50
(T/F) Other immunosuppressive agents have been shown to reduce ADA development, including corticosteroids and B-cell depleting agents (e.g., rituximab)
True
51
Long term treatment with immunosuppressants is desirable
False
52
What helps in the priori predication of immunogenicity?
T cell epitopes
53
what are T cell epitopes?
peptide sequences that are presented by MHC and bind to the T-cell Receptor
54
Increased content of _____ generally leads to a higher risk of immunogenicity
T cell epitopes
55
____ tools are available that can be used to ‘de-risk’ molecules by identifying potential immunogenicity liabilities These tools general focus on T-cell and B-cell epitopes
In silico
56
Can we predict what individuals will develop ADA just the risks based on the cumulative data from complex mathematical models?
No
57
(T/F) Complex mathematical models have been developed to predict immunogenicity in patients and it is extremely new
True
58
Hemophilia A
X-linked clotting disorder characterized by deficiency or absence of coagulation FVIII
59
Factor VIII (FVIII)
blood clotting protein; stops bleeding
60
Low FV III (less than 6%) means the pt has
moderate- severe case of Hemophilia A
61
Characterization of Hemophilia A
spontaneous bleeding, mainly into large joints
62
Standard of care of Hemophilia A
replacement therapy with plasma-derived or recombinant FVIII
63
(T/F) Severe hemophilia A patients have a high incidence of neutralizing antibody development
True
64
Why do roughly 1/3 of moderate and severe hemophilia A patients developed inhibitory ADA within 50 days of initiating treatment?
-These pts have genetic defects in FVIII, which did not develop central tolerance to FVIII, therefore it is recognized as a foreign protein - Also, Impurities in plasma derived products and alternative post-translational modifications in recombinant products
65
clinical protocols to restore tolerance to FVIII
Bonn Protocol, Van Creveld Protocol, Malmo Protocol
66
what is tolerance?
the prevention of an immune response of a particular antigen
67
(T/F) Tolerance is antigen-specific
T
68
(T/F) Tolerance to one protein should not induce hypo-responsiveness to an unrelated drug
T
69
(T/F) Tolerance involves both cellular responses and depletion of ADA
True
70
Cellular responses of tolerance
Decreased dendritic cell maturation Increased regulatory T cells Decreased memory B cells
71
co-exposure of FIII and phosphatidylserine induces
immunologic tolerance, antigen specificity (reduced ADA against only FVIII), increase Treg, decrease dendritic cell activation, and reduce memory B cells
72
Apoptosis must result in ____ to prevent ____
tolerance, autoimmunity
73
Exposure of _____ is a key step in apoptosis that promotes engulfment by phagocytes
Phosphatidylserine
74
Phosphatidylserine is confined where in the cell membranes?
Inner leaflet
75
Rapamycin (Sirolimus)
potent immunosuppressive mTOR inhibitor
76
Function of Rapamycin (Sirolimus)
blocks T, B cell activation
77
(T/F) Co encapsulation of rapamycin and antigen reduced ADA development and robust tolerance induction was observed
T
78
Pegloticase
PEGylated uricase used to treat gout patients that don’t respond to other treatments
79
Immunogenicity of Pegloticase
Very high
80
T/F Reduced ADA development occurred against pegloticase and allowed sustained improvement in disease severity of gout pts
T

Immunology Exam 3 (7 decks)

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