BL 02-25-14 10-11am Immunomodulators - Cohen Flashcards
Immunomodulation
use of drugs (alone or in combo with other maneuvers) to change the function of all or part of the immune system
Categories of Immunomodulators
- NSAIDs
- Disease-modifying antirheumatic drugs (DMARDs).
- Glucocorticoids.
- Biological response modifiers.
- Tumor-specific monoclonal antibodies.
- Other antibodies.
- Miscellaneous drugs.
Biological Response Modifiers
- loose class of substances targeted mostly at cytokines or their receptors, or at cellular communication molecules
Different kinds of Biological Response Modifiers
- antagonists or agonists
- may be genetically-engineered receptor antagonists. or cloned, mass-produced normal gene products
- many are antibodies to various components of the immune/inflammatory system
- -> stimulate, inhibit, or opsonize (depending on designer’s intentions)
Monoclonal antibodies (mAb) - overview
- Dream manufactoring: can be manufacture under ideal conditions, any quantity can be made, with complete uniformity of product
- BUT, very expensive
Monoclonal antibodies (mAb) - what are they
- antibodies derived from the progengy of a single B cells, that has been fused with multiple myeloma tumor cells (Hybridoma)
- resultant hybrid line can grow forever in culture like its tumor parent, but can make the specific antibody of its B cell parent
Murine mAbs
- made from immunized mice
- omab
-omab
- made from immunized mice
- murine mAbs
chimeric mAbs
- mAbs engineered at DNA level to have mouse
VL & VH domains, but human C domains - less likely to be recognized by pt’s own immune system
-ximab
-ximab
- chimeric mAbs
- mAbs engineered at DNA level to have mouse
VL & VH domains, but human C domains - less likely to be recognized by pt’s own immune system
humanized mAbs
- mAbs which have only the CDR’s of the V domains are from the mouse
- zumab
- zumab
- humanzied mAb
- mAbs which have only the CDR’s of the V domains are from the mouse
human mAbs
- fully human mAbs (no mouse parts)
- umab
-umab
- human mAbs (fully human, with no mouse parts)
Targets of mAbs
- Several mAb to TNFalpha
- glycoprotein IIb/IIIa receptor (platelet aggregation)
- IL-2 receptor
- CD11s (LFA-1) [T cell activation]
- human IgE
- alpha-4 integrin (lymphocyte migration)
- IL-12, IL-23
- IL-6 receptor
- B-lymphocyte stimulator (BLyS)
Pregnancy & mAbs
mAbs are IgG, so will cross placenta
So, PEGylate them - polyethylene glycal (does not cross placenta)
NK (natural killer) cells - overview
- large granular lymphocytes (LGL)
- make up 5010% of blood lymphocyte cells
- killers with mechanisms available similar to those of CTL, but do not have rearranged V(D)J gene and are not thymic-derived
NK cells - two tricks
- a few NK receptors which recognize molecules on surface of “stress” or dysregulated cells (virally-infection or tumor), which they then kill
- -> part of the innate immune system - NK receptors for Fc end of IgG (FCgammaR), giving them a second antibody-dependent way to interact with target cells = antibody-dependent cell-mediated cytotoxicity (ADCC)
- -> part of the adaptive immune system
ADCC (antibody-dependent cell-meidated cytotoxicity)
- don’t know much about its role in normal immunity
Used in the case of tumor cells that do NOT express markers that NK cells will recognized via NK receptors
thus, NK cells need antibody help to recognize & kill such tumor cells
Mechanism of ADCC
- IgG antibody binds to the target cell (but can’t kill it)
- NK cell (LGL) binds to Fc end of the antibody
- Just like a killer T cell, NK cell is now triggered & delivers lethal signals to the target
- Target dies by apoptosis
s blood leukocytes can be used; not MHC-restricted like CTL-mediated killing is
Ways to use ADCC for treatment
- Many new therapeutic mAbs (for immunopathology & cancer) work by triggering ADCC
Passive antibody therapy in cancer
- Uses antibody to tumor-associated antigens
- Several mAbs already available
Mechanisms of passive mAb therapy in cancer
- A few activate complement, & tumor is lysed or phagocytosed
- More often they invoke ADCC
Abs can be tagged w/ poison such as calicheamicin or diphtheria toxin, or a radioisotope (= immunotoxins)
- -> highly-targeted delivery of toxic moiety
- May be used as both an imaging & therapeutic drug, depending on which radioisotope is attached.
passive mAb therapy in cancer – Targets
- CD20 (non-HL, CLL)
- CD33 (AML)
- CD52 (B-CLL)
- EGFR - HER2
- VEGF
- CTLA-4 (melanoma)
- PD-1 (effector CTL inhibitor)
BiTE antibodies for cancer
1VL + 1VH for CD3 (signaling component of T cell receptr
PLUS
1VL + 1VH for tumor antigen (CD19)
- -> grabs onto T cell (activating it)
- -> grabs onto tumor (brings T cell to tumor so it can kill it)
*No specificity needed here, just pulling them together to make T kill tumor
Chimeric antigen receptor (CAR) & cancer
Takes T cells from cancer pt & transform with lentivirus vectors with a CAR (chimeric antigen receptor)
CDRs from high affinity mAb (to tumor Ag) PLUS chain through T cell membrane PLUS CD3 (activate T cell)
==> gives T cell new receptor
- on outside = highly specific, high affinity Ab to bind tumor cell
- on inside = what you need to activate T to become cytotoxic
take out T from cancer patient, engineer, grow up, add back into pt
==> SUPER CHARGED T CELLS
Other BRMs - Interleukin-2
Used in renal cancer and melanoma treatment with
other agents.
Other BRMS - Interferon-gamma
Approved to treat chronic granulomatous disease & osteopetrosis.
Other BRMS - G-CSF
Used to treat lymphomas, leukemias, and in bone
marrow transplantation.
Also as an adjunct in cancer chemotherapy
Other BRMS - GM-CSF
Used to treat leukemias, and in bone marrow
transplantation.
denosumab
Human mAb against RANK ligand (RANKL).
For use in certain osteoporosis.
Stimulation of RANK causes osteoclast maturation, which denosumab blocks.
IVIg
Originally used only in immunodeficiency disease, IVIG is now widely used in a variety of conditions including many autoimmune diseases.
- Stimulated inhibitory receptors on phagocytes
Traditional drugs (ex. corticosteroids) vs. BRM
Corticosteroids
= many side effects (not suprising)
BRM = greater specificity = mechanism-based design = many side affects (unanticipated) = not always effective (unanticipated) = expensive!!!
Drugs used in Organ Transplantation
- less needed nowadays to get a perfect match, b/c surgeons rely on highly effective immunosupressive therapy
- purpose of treatment is to prevent rejection & drugs are very good at doing this
- thus, not the main problem nowadays; rather, other consequences of these drugs are the prob
= inherently toxic, can increase cancer risk & risk of opportunistic infection
Main drugs in Organ Transplantation
Azathioprine Mycophenolate mofetil Glucocorticoids Cyclosporine-A Tacrolimus Sirolimus: (rapamycin) Anti-thymocyte globulin (ATGAM) mAbs to CD3 and the IL-2 receptor Miscellaneous drugs
Azathioprine
- decreases DNA synthesis & mRNA transcription
- Gradually being replaced by Mycophenolate mofetil
Mycophenolate mofetil
Less toxic & same mode of action as azathioprine (decreased DNA synthesis & mRNA transcription)
Glucocorticoids
- Essential anti-inflammatories in transplantation
- Usually start with very high dose, taper ASAP, discontinue if possible
- High doses can also be used briefly for threatened rejection episodes
Cyclosporine-A
- Primarily decreases IL-2 production
- Thus it is synergistic with glucocorticoids which, by down-regulating macrophage function as APCs, lessen stimulation of T cells
Tacrolimus
- Can synergize with cyclosporine-A.
- The combo decreases both synthesis & response to IL-2
Sirolimus: (rapamycin)
- New relative of cyclosporine.
- It binds FKBP-12 as does tacrolimus, but the complex has no effect on calcineurin
- Instead, inhibits kinase called Target of Rapamycin (mTOR) which is needed for T cell activation.
- Approved in kidney transplantation.
Anti-thymocyte globulin (ATGAM)
- Made in horses,& now rabbits immunized with human thymocytes
- Useful as a part of regimen to prepare recipients for bone marrow transplantation and in acute organ rejection
mAbs to CD3 and the IL-2 receptor
- Both can be gotten humanized, though common one, Muromomab, is simply a mouse mAb against CD3 (the same as the well-known diagnostic monoclonal OKT3)
- Replacing anti-thymocyte globulin but are expensive
- Too much anti-CD3 can destroy so many T cells at once that the patient undergoes a “cytokine storm”, something like the flu but 1000 times worse
Miscellaneous drugs in organ transplantation
Drugs may be necessary for infection control, pain management, nutritional support, etc.
