ADAPTIVE IMMUNE RESPONSE TO BIOTHERAPEUTICS Flashcards
WHAT IS IMMUNOGENICITY?
HOST IMMUNE RESPONSE AGAINST A THERAPEUTIC PROTEIN / Host immune system recognizes the drug as ‘non-self’
WHERE IS IMMUNOGENICITY STUDIED IN?
FORMATION OF ANTI-DRUG ANTIBODIES (ADA)
WHERE IS IMMUNOGENICITY LOCATED ON FDA A APPROVED LABEL?
ADVERSE REACTIONS
What is the variability of immunogenicity?
Highly variable
Immunogenicity incidence ranges from __% to nearly __% of subjects
0, 50
(T/F) Immunogenicity is extremely difficult to predict and mitigate
True
Data is usually stratified by ___ status to allow easy identification of the impact of immunogenicity
ADA
ADA does what to both efficacy and safety?
It reduces them
ADA reduce both efficacy and safety through which mechanisms?
Neutralizing drug activity, accelerating drug elimination and formation of immune complexes
Types of anti-drug antibodies (ADA)
Binding (non NAb) and Neutralizing (NAb)
What happens in the binding class of ADA?
Non-NAb interacts with the drug molecule but does not inhibit its binding to the pharmacologic target.
Where is the non- NAb located?
It is away from the active site
What happens in the neutralizing class of ADA?
NAb directly blocks interaction of drug with its pharmacologic target
Where is the NAb located?
It is located at the active site
Binding has an impact on
pharmacokinetics and safety
Impact of Neutralizing
Loss of efficacy/ impact on pharmacokinetics and safety
Both binding and neutralizing can be categorized as ____
clearing
clearing ADA are detected based on their what?
effects on pharmacokinetics
Non clearing ADA is also referred as
sustaining ADA
What happens when there’s a development of ADA?
Rapid decrease in plasma drug concentration
What happens when there’s multiple dosing of ADA?
Decrease in plasma concentration
Factors that influence Immunogenicity
biologic molecule, biologic product, antigen, and patient
biologic molecule
- sequence (rodent vs human sequence)
- allotype
- structure
biologic product
- formulation
- dose
- route of administration
- frequency of administration
- aggregates and impurities
patient related factors
disease type
disease activity
concomitant therapies
genetics
antigen
cell bound or soluble
Immunogenicity is largely thought to be a __-cell dependent phenomenon
T
Presentation to ____ cells leads to ADA generation
T helper
Presentation to ___cells limits ADA generation
Treg
___ and ____are thought to drive whether an immunogenic response occurs
Tepitopes, Tregitopes
___ the human content of the primary (amino acid) sequence decreases immunogenicity
increasing
Which antibody is the most immunogenic?
mouse or murine
Which antibody is the least immunogenic?
human/humanized
which antibody is moderately immunogenic?
chimeric
T/F rank antibody from most immunogenic to least immunogenic
Mouse (murine) > Chimeric > Humanized > Human
Muromanab
mouse antibody
Rituximab
chimeric antibody
trastuzumab
humanized antibody
adalimumab
human antibody
____ IgG sequences are more readily recognized as ‘non-self’ by the immune system
Non-human
How are Monoclonal antibodies (mABs) developed now?
humanized or fully human
mAbs with mouse Fc are eliminated ___ rapidly and need ____ frequent dosing
more, more
Which route of administration is more immunogenic than intravenous dosing?
Subcutaneous & Intramuscular injections
Subcutaneous & Intramuscular injections puts the drugs near antigen-presenting cells, __________
dendritic cells
Proteins must travel through ________ to reach the systemic circulation following SC/IM dosing
lymph nodes
Injections may lead to ____ inflammation, which further primes the immune system for response
local
T/F anti-inflammatory drugs, such as low-dose methotrexate, have been shown to reduce the development of anti-drug antibodies in patients.
True
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
(T/F) In combination with adalimumab (Humira, anti-TNF), methotrexate reduces ADA incidence in a dose-dependent manner and increases serum adalimumab concentrations
True
(T/F) Other immunosuppressive agents have been shown to reduce ADA development, including corticosteroids and B-cell depleting agents (e.g., rituximab)
True
Long term treatment with immunosuppressants is desirable
False
What helps in the priori predication of immunogenicity?
T cell epitopes
what are T cell epitopes?
peptide sequences that are presented by MHC and bind to the T-cell Receptor
Increased content of _____ generally leads to a higher risk of immunogenicity
T cell epitopes
____ 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
Can we predict what individuals will develop ADA just the risks based on the cumulative data from complex mathematical models?
No
(T/F) Complex mathematical models have been developed to predict immunogenicity in patients and it is extremely new
True
Hemophilia A
X-linked clotting disorder characterized by deficiency or absence of coagulation FVIII
Factor VIII (FVIII)
blood clotting protein; stops bleeding
Low FV III (less than 6%) means the pt has
moderate- severe case of Hemophilia A
Characterization of Hemophilia A
spontaneous bleeding, mainly into large joints
Standard of care of Hemophilia A
replacement therapy with plasma-derived or recombinant FVIII
(T/F) Severe hemophilia A patients have a high incidence of neutralizing antibody development
True
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
clinical protocols to restore tolerance to FVIII
Bonn Protocol, Van Creveld Protocol, Malmo Protocol
what is tolerance?
the prevention of an immune response of a particular antigen
(T/F) Tolerance is antigen-specific
T
(T/F) Tolerance to one protein should not induce hypo-responsiveness to an unrelated drug
T
(T/F) Tolerance involves both cellular responses and depletion of ADA
True
Cellular responses of tolerance
Decreased dendritic cell maturation
Increased regulatory T cells
Decreased memory B cells
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
Apoptosis must result in ____ to prevent ____
tolerance, autoimmunity
Exposure of _____ is a key step in apoptosis that promotes engulfment by phagocytes
Phosphatidylserine
Phosphatidylserine is confined where in the cell membranes?
Inner leaflet
Rapamycin (Sirolimus)
potent immunosuppressive mTOR inhibitor
Function of Rapamycin (Sirolimus)
blocks T, B cell activation
(T/F) Co encapsulation of rapamycin and antigen reduced ADA development and robust tolerance induction was observed
T
Pegloticase
PEGylated uricase used to treat gout patients that don’t respond to other treatments
Immunogenicity of Pegloticase
Very high
T/F Reduced ADA development occurred against pegloticase and allowed sustained improvement in disease severity of gout pts
T
