Immunomodulators Flashcards
- Define monoclonal antibodies, and describe in principle how they are made.
The typical monoclonal antibody ► derives from the progeny of a single B cell, that has been fused with a multiple myeloma tumor cell; the resultant hybrid line can grow forever in culture like its tumor parent, but make the specific antibody of its B cell parent. Thousands are used in labs aroun d the planet, and a t least 60 are already drugs .
- Discuss the use of monoclonal antibodies as anti-inflammatory agents.
BIOLOGICAL RESPONSE MODIFIERS. These are a loose class of substances targeted mostly at cytokines or their receptors, or at cellular communication and signaling molecules . They can be antagonists or agonists. They can be genetically-engineered receptor antagonists. And they can be cloned, mass-produced normal gene products.
**Many of these agents are antibodies to various components of the immune or inflammatory system (which stimulate, inhibit, or opsonize , depending on the designer’s intentions).
- Compare and contrast murine, chimeric, humanized, and human monoclonal antibodies. Discuss which might have disadvantages when used in human patients, and the reason for that.
The ones directly derived from immunized mice are called_______.
The ones that have engineered DNA to have mouse VL and VH domain, but C domains are called_______.
The first monoclonals were made using B cells directly derived from immunized mice; such antibodies are murine [-omab] (e.g., ibritumomab).
Some mAbs have been engineered at the DNA level to have the mouse VL and VH domains, but human C domains; these are chimeric, [- ximab] and less likely to be recognized by your patient’s own immune system.
Going further, there are monoclonals which are humanized [-zumab] ;only the CDR’s of the V domains are from the mouse.
Finally, fully human [- umab] monoclonals are now becoming common.
- 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.
They have a way of killing similar to those of CTL, but they don’t have rearranged _____ genes and are not _______ derived.
What do NK recognize in the surface of stressed cell or dysregulated cells?
NK are part of what immune system?
NK (natural killer) cells are ►large granular lymphocytes ( LGL ) which make up 5 - 10% of blood lymphocytic cells. They are killers with mechanisms available similar to those of CTL, but they do not have rearranged V(D)J genes and are not thymus-derived.
They have a few NK receptors which recognize molecules (which you could call DAMPs) on the surface of ‘stressed’ or dysregulated cells, such as virally-infected cells or many tumors, which they then kill; therefore, they are part of the innate immune system.
- 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.
- Describe how a monoclonal antibody against a T cell surface molecule could enhance the activity of a CTL
A SPECIAL KILLING MECHANISM. ► It’s called antibody-dependent cell-mediated cytotoxicity , or ADCC.
Here’s an example of the phenomenon, then we’ll explain it. Not all tumor cells express the markers that NK cells recognize via NK receptors (you’d guess that tumors would gradually be selected to downregulate such markers). Let’s take cells from such a tumor. Antibody against some specific protein on the tumor cells is added to them in culture; the antibody binds but has no observable effect. Normal blood leukocytes (which include LGL) are now added; the tumor cells are killed by induced apoptosis. If you hadn’t added both antibody and the LGL, nothing would have happened, so the phenomenon is called ADCC.
Anyone’s leukocytes can be used; the phenomenon is not MHC - restricted the way CTL - mediated killing is. (NK cells do have a generic receptor for MHC Class I, but it’s inhibitory; so they leave MHC-high cells to be dealt with by CTL. Clever!)
- 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.
► ADCC works because NK cells also have receptors for the Fc end of IgG (FcγR), and so they have a second, antibody-dependent, way to interact with target cells.
The mechanism of ADCC is this: IgG antibody binds to the target cell, then the NK cell binds to the Fc end of the antibody. Just like a killer T cell, the NK cell is now triggered and delivers lethal signals to the target, which dies by apoptosis. We know that many of the new therapeutic monoclonal antibodies (used to modulate the immune response, or treat cancer) work by triggering ADCC. The normal role of ADCC has been hard to define; recently it has been reported that some HIV elite controllers have particularly strong early ADCC that destroys their HIV - infected cells .
- Discuss the use of modified (drugs, isotopes) monoclonal antibodies in tumor diagnosis or therapy.
PASSIVE ANTIBODY THERAPY IN CANCER. Antibody to tumor - associated antigens should be useful, and quite a few monoclonal antibodies (mAb) are already available.
A few activate complement, and the tumor is lysed or phagocytosed; ► more often they invoke ADCC.
Antibodies can also be tagged with a poison or a radioisotope (such modified antibodies are called immunotoxins). They provide highly-targeted delivery of the toxic moiety. At least one mAb is available for use as both an imaging and a therapeutic dr ug, depending on which radioisotope is attached.
- Discuss strategies for use of monoclonal antibodies to modify immune responses.
- Describe a generic BiTE (bi-specific T cell engager) and speculate on possible use of BiTEs with CD3 and any other binding ability.
- Discuss how the use of BRMs, which target known pathways of the immune system, can lead to serious and often predictable side effects
