BL - Immunomodulators

Question 1

LO 1. Define monoclonal antibodies and describe how they are made.

Answer 1

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

Question 2

LO 2. Discuss the use of monoclonal antibodies as anti-inflammatory agents.

Answer 2

?

Question 3

LO 3. Compare and contrast murine, chimeric, humanized, and human monoclonal antibodies. Which might have disadvantages when used in human patients and why?

Answer 3

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?

Question 4

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.

Answer 4

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.

Question 5

LO 5. Discuss the use of growth factors in bone marrow transplantation.

Answer 5

?

Question 6

LO 6. Describe how a monoclonal antibody against a T cell surface molecule could enhance the activity of a CTL.

Answer 6

ex: ipilimumab. Binds CTLA-4 and prevents its inhibitory signal, so CTLs are activated. Used in melanoma.

Question 7

LO 7. Discuss the use of modified (drugs, isotopes) monoclonal antibodies in tumor diagnosis or therapy.

Answer 7

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

Question 8

What is immunomodulation?

Answer 8

use of drugs to change the function of the immune system

Question 9

Name the 7 categories of immunomodulators.

Answer 9

1. NSAIDs
2. DMARDs
3. glucocorticoids
4. biological response modifiers
5. tumor-specific monoclonal Abs
6. other Abs
7. misc. drugs

Question 10

What are biological response molecules?

Answer 10

substances that target cytokines, their receptors, cellular communication molecules, or signaling molecules

Question 11

Biological response molecules can be ____, ____, ____, or ____.

Answer 11

antagonists; agonists; Abs; normal gene products

Question 12

What is the main problem with mAbs?

Answer 12

cost

Question 13

How are mAbs made?

Answer 13

transgenic animals (secreted into milk) or transgenic plants

Question 14

The typical mAb derives from _____ that has been fused with _____.

Answer 14

a single B cell; a multiple myeloma tumor cell

Question 15

Abs from immunized mice are called _____ and end in ____.

Answer 15

murine; -omab

Question 16

Abs that have mouse VL and VH domains but human C domains are called _____ and end in ____.

Answer 16

chimeric; -ximab

Question 17

Abs that only have CDRs from the V domain from a mouse are called _____ and end in ____.

Answer 17

humanized; -zumab

Question 18

Fully human Abs end in ____.

Answer 18

-umab

Question 19

What are NK cells?

Answer 19

large granular lymphocytes (LGL) that do not have V(D)J genes; part of innate immunity

Question 20

What does ADCC stand for?

Answer 20

antibody dependent cell-mediated cytotoxicity

Question 21

What is the main distinguishing feature of ADCC?

Answer 21

NK cells kill w/o restriction to MHC

Question 22

How does ADCC work?

Answer 22

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

Question 23

How are passive Abs used to treat CA?

Answer 23

antibodies are made to tumor-associated antigens, which activate complement or ADCC or die via immunotoxins

Question 24

What does BiTE stand for?

Answer 24

Bispecific T-cell Engager

Question 25

How does BiTE work?

Answer 25

2 single-chain engineered antibodies, one against CD19 and one against CD3, bind to T cells in lymphoma and cause tumor cell death

Question 26

What drug uses BiTE?

Answer 26

blinatumomab (Blincyto)

Question 27

What does CAR stand for?

Answer 27

chimeric antigen receptor

Question 28

How are CARs used to treat CA?

Answer 28

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

Question 29

Name 8 major drugs used in organ transplantation and how they work.

Answer 29

1. azathioprine (decreased DNA synth. and mRNA transc.)
2. mycophenylate mofetil (same as azathioprine, less tox)
3. glucocorticoids (anti-inflamm)
4. cyclosporine A (decrease IL-2 production and lessen stim of T cells)
5. tacrolimus (synergizes with cyclosporine A)
6. sirolimus (rapamycin- binds FKBP-12 to inibit mTOR and T cell activation)
7. anti-thymocyte globulin (ATGAM)
8. mAbs (against CD3 and IL-2)