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Immunology Exam 3 > ADAPTIVE IMMUNE RESPONSE TO BIOTHERAPEUTICS > Flashcards

ADAPTIVE IMMUNE RESPONSE TO BIOTHERAPEUTICS Flashcards

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
Q

patient related factors

A

disease type
disease activity
concomitant therapies
genetics

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26
Q

antigen

A

cell bound or soluble

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27
Q

Immunogenicity is largely thought to be a __-cell dependent phenomenon

A

T

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28
Q

Presentation to ____ cells leads to ADA generation

A

T helper

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29
Q

Presentation to ___cells limits ADA generation

A

Treg

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30
Q

___ and ____are thought to drive whether an immunogenic response occurs

A

Tepitopes, Tregitopes

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31
Q

___ the human content of the primary (amino acid) sequence decreases immunogenicity

A

increasing

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32
Q

Which antibody is the most immunogenic?

A

mouse or murine

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33
Q

Which antibody is the least immunogenic?

A

human/humanized

34
Q

which antibody is moderately immunogenic?

A

chimeric

35
Q

T/F rank antibody from most immunogenic to least immunogenic

A

Mouse (murine) > Chimeric > Humanized > Human

36
Q

Muromanab

A

mouse antibody

37
Q

Rituximab

A

chimeric antibody

38
Q

trastuzumab

A

humanized antibody

39
Q

adalimumab

A

human antibody

40
Q

____ IgG sequences are more readily recognized as ‘non-self’ by the immune system

A

Non-human

41
Q

How are Monoclonal antibodies (mABs) developed now?

A

humanized or fully human

42
Q

mAbs with mouse Fc are eliminated ___ rapidly and need ____ frequent dosing

A

more, more

43
Q

Which route of administration is more immunogenic than intravenous dosing?

A

Subcutaneous & Intramuscular injections

44
Q

Subcutaneous & Intramuscular injections puts the drugs near antigen-presenting cells, __________

A

dendritic cells

45
Q

Proteins must travel through ________ to reach the systemic circulation following SC/IM dosing

A

lymph nodes

46
Q

Injections may lead to ____ inflammation, which further primes the immune system for response

A

local

47
Q

T/F anti-inflammatory drugs, such as low-dose methotrexate, have been shown to reduce the development of anti-drug antibodies in patients.

A

True

48
Q

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).

A

True

49
Q

(T/F) In combination with adalimumab (Humira, anti-TNF), methotrexate reduces ADA incidence in a dose-dependent manner and increases serum adalimumab concentrations

A

True

50
Q

(T/F) Other immunosuppressive agents have been shown to reduce ADA development, including corticosteroids and B-cell depleting agents (e.g., rituximab)

A

True

51
Q

Long term treatment with immunosuppressants is desirable

A

False

52
Q

What helps in the priori predication of immunogenicity?

A

T cell epitopes

53
Q

what are T cell epitopes?

A

peptide sequences that are presented by MHC and bind to the T-cell Receptor

54
Q

Increased content of _____ generally leads to a higher risk of immunogenicity

A

T cell epitopes

55
Q

____ 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

A

In silico

56
Q

Can we predict what individuals will develop ADA just the risks based on the cumulative data from complex mathematical models?

A

No

57
Q

(T/F) Complex mathematical models have been developed to predict immunogenicity in patients and it is extremely new

A

True

58
Q

Hemophilia A

A

X-linked clotting disorder characterized by deficiency or absence of coagulation FVIII

59
Q

Factor VIII (FVIII)

A

blood clotting protein; stops bleeding

60
Q

Low FV III (less than 6%) means the pt has

A

moderate- severe case of Hemophilia A

61
Q

Characterization of Hemophilia A

A

spontaneous bleeding, mainly into large joints

62
Q

Standard of care of Hemophilia A

A

replacement therapy with plasma-derived or recombinant FVIII

63
Q

(T/F) Severe hemophilia A patients have a high incidence of neutralizing antibody development

A

True

64
Q

Why do roughly 1/3 of moderate and severe hemophilia A patients developed inhibitory ADA within 50 days of initiating treatment?

A

-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
Q

clinical protocols to restore tolerance to FVIII

A

Bonn Protocol, Van Creveld Protocol, Malmo Protocol

66
Q

what is tolerance?

A

the prevention of an immune response of a particular antigen

67
Q

(T/F) Tolerance is antigen-specific

A

T

68
Q

(T/F) Tolerance to one protein should not induce hypo-responsiveness to an unrelated drug

A

T

69
Q

(T/F) Tolerance involves both cellular responses and depletion of ADA

A

True

70
Q

Cellular responses of tolerance

A

Decreased dendritic cell maturation
Increased regulatory T cells
Decreased memory B cells

71
Q

co-exposure of FIII and phosphatidylserine induces

A

immunologic tolerance, antigen specificity (reduced ADA against only FVIII), increase Treg, decrease dendritic cell activation, and reduce memory B cells

72
Q

Apoptosis must result in ____ to prevent ____

A

tolerance, autoimmunity

73
Q

Exposure of _____ is a key step in apoptosis that promotes engulfment by phagocytes

A

Phosphatidylserine

74
Q

Phosphatidylserine is confined where in the cell membranes?

A

Inner leaflet

75
Q

Rapamycin (Sirolimus)

A

potent immunosuppressive mTOR inhibitor

76
Q

Function of Rapamycin (Sirolimus)

A

blocks T, B cell activation

77
Q

(T/F) Co encapsulation of rapamycin and antigen reduced ADA development and robust tolerance induction was observed

A

T

78
Q

Pegloticase

A

PEGylated uricase used to treat gout patients that don’t respond to other treatments

79
Q

Immunogenicity of Pegloticase

A

Very high

80
Q

T/F Reduced ADA development occurred against pegloticase and allowed sustained improvement in disease severity of gout pts

A

T

Immunology Exam 3 (7 decks)

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