BL - Immunomodulators Flashcards
LO 1. Define monoclonal antibodies and describe how they are made.
mAbs: progeny Abs from a single B cell clone that has been fused with a multiple myeloma tumor cell (very specific to a certain target). Made from transgenic animals secreted into milk, or in transgenic plants
LO 2. Discuss the use of monoclonal antibodies as anti-inflammatory agents.
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LO 3. Compare and contrast murine, chimeric, humanized, and human monoclonal antibodies. Which might have disadvantages when used in human patients and why?
murine: derived from mice (-omab)*
chimeric: mouse VL and VH with human C domain (-ximab)*
humanized: only CDRs of V domains from mouse (-zumab)***
human: (-umab)
* ** non-human = possible problems?
LO 4. Define NK cells and ADCC. Discuss the effect of Class I MHC expression levels on susceptibility of target cells to CTL and NK cells, respectively. Describe the mechanism for ADCC.
NK cell = innate immunity; lymphocytes w/o VDJ genes; use ADCC (antibody-dependent cytotoxicity) to recognize IgG and induce apoptosis in infected cells. Not MHC-restricted like CTL-mediated killing.
LO 5. Discuss the use of growth factors in bone marrow transplantation.
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LO 6. Describe how a monoclonal antibody against a T cell surface molecule could enhance the activity of a CTL.
ex: ipilimumab. Binds CTLA-4 and prevents its inhibitory signal, so CTLs are activated. Used in melanoma.
LO 7. Discuss the use of modified (drugs, isotopes) monoclonal antibodies in tumor diagnosis or therapy.
Abs to tumor-associated antigens can activate complement or ADCC; ibritumomab tiuxetan can be used to fluorescently ID and then treat tumors; ipilimumab is used to bind to VEGF
What is immunomodulation?
use of drugs to change the function of the immune system
Name the 7 categories of immunomodulators.
- NSAIDs
- DMARDs
- glucocorticoids
- biological response modifiers
- tumor-specific monoclonal Abs
- other Abs
- misc. drugs
What are biological response molecules?
substances that target cytokines, their receptors, cellular communication molecules, or signaling molecules
Biological response molecules can be ____, ____, ____, or ____.
antagonists; agonists; Abs; normal gene products
What is the main problem with mAbs?
cost
How are mAbs made?
transgenic animals (secreted into milk) or transgenic plants
The typical mAb derives from _____ that has been fused with _____.
a single B cell; a multiple myeloma tumor cell
Abs from immunized mice are called _____ and end in ____.
murine; -omab
Abs that have mouse VL and VH domains but human C domains are called _____ and end in ____.
chimeric; -ximab
Abs that only have CDRs from the V domain from a mouse are called _____ and end in ____.
humanized; -zumab
Fully human Abs end in ____.
-umab
What are NK cells?
large granular lymphocytes (LGL) that do not have V(D)J genes; part of innate immunity
What does ADCC stand for?
antibody dependent cell-mediated cytotoxicity
What is the main distinguishing feature of ADCC?
NK cells kill w/o restriction to MHC
How does ADCC work?
IgG Ab binds to target cell
NK cell binds to the Fc end of the Ab (FcgammaR)
NK cell is activated and kills cell via apoptosis
How are passive Abs used to treat CA?
antibodies are made to tumor-associated antigens, which activate complement or ADCC or die via immunotoxins
What does BiTE stand for?
Bispecific T-cell Engager
How does BiTE work?
2 single-chain engineered antibodies, one against CD19 and one against CD3, bind to T cells in lymphoma and cause tumor cell death
What drug uses BiTE?
blinatumomab (Blincyto)
What does CAR stand for?
chimeric antigen receptor
How are CARs used to treat CA?
bind them to T cells removed from CA pts using lentiviruses, then replace the cells; this allows transformed CTLs to bind tumor targets with high affinity and specificity w/o MHC restriction
Name 8 major drugs used in organ transplantation and how they work.
- azathioprine (decreased DNA synth. and mRNA transc.)
- mycophenylate mofetil (same as azathioprine, less tox)
- glucocorticoids (anti-inflamm)
- cyclosporine A (decrease IL-2 production and lessen stim of T cells)
- tacrolimus (synergizes with cyclosporine A)
- sirolimus (rapamycin- binds FKBP-12 to inibit mTOR and T cell activation)
- anti-thymocyte globulin (ATGAM)
- mAbs (against CD3 and IL-2)
