Immunomodulators

Question 1

monoclonal antibodies (mAb)

Answer 1

the drug product of a single B cell that is fused/hybridized with a multiple myeloma tumor cell →

you get a hybrid line that is immortal (like its tumor parent) but also make the specific antibody of its B cell parent (monoclonal antibodyproducing cells)! = Hybridoma →

After they make the Ab you want, you take it out of the well, and use it for your purposes→

mAb work by triggering ADCC (more on this in later objective)

5

Question 2

Examples of monoclonal antibodies as anti-inflammatory agents.

Answer 2

Infliximab - chimeric Ab against TNFα → approved for a lot of inflammatory diseases

Tocilizumab - Anti IL-6 receptor → approved for RA (inflammation)

Question 3

Murine mAb

- suffix?

Answer 3

[-omab]

The first monoclonals made using B cells directly derived from immunized mice;

Question 4

Chimeric mAb

Answer 4

[-ximab]

mouse VL and VH domains (V regions)
human C domains

Question 5

Humanized mAb

Answer 5

[-zumab]

only the CDR’s of the V domains are from the mouse.

Question 6

Fully human mAb

Answer 6

[-umab]

made entirely of human amino acids

Question 7

NK (natural killer) cells:

Answer 7

Large granular lymphocytes (LGL) which make up 5-10% of blood lymphocytic cells.

○ NK receptors recognize molecules 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.

○ They have a second cytotoxic trick available: a special killing mechanism → ADCC

Question 8

How are NK cells different from CTLs?

Answer 8

○ NK cells are killers with mechanisms VERY similar to those of CTL, but they do not have rearranged V(D)J genes and are not thymic-derived.

Question 9

Antibody-dependent cell-mediated cytotoxicity (ADCC):

Answer 9

Let’s take cells from a tumor that expresses markers that NK cells recognize via NK receptors → add antibodies (ie: IgG) that can bind to target tumor cells → no effect → add normal blood leukocytes (which include NK cells) → NK cells binds to the Fc end of the antibody → Just like a Killer T cells, NK cells trigger tumor cell death via delivery of lethal signals → induced apoptosis

(If you hadn’t added both antibody and the NK cells, nothing would have happened, so the phenomenon is called ADCC.)

Question 10

Whats unique about the way that ADCC work?

Answer 10

§ Anyone’s leukocytes can be used; the phenomenon is not MHC-restricted the way CTL-mediated killing is.

§ 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.

§ We know that many of the new therapeutic monoclonal antibodies (used to modulate the immune response, or treat cancer) work by triggering ADCC.

Question 11

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

Answer 11

Concept was named BiTE for Bispecific T-cell Engager. (Engages CTL)

-Couple together two single-chain engineered antibodies, one against CD19 and one against CD3 →
T cells can bind via their CD3 to CD19+ of B cell lymphoma cells.

This allows a transformed CTL to bind a tumor target with high affinity and chosen specificity, and, like an antibody, no MHC-restriction, and then be triggered via its normal TCR-associated pathway to become a fully-cytotoxic cell.

Question 12

what type of mAb is it and what does it target?

- Rituximab

Answer 12

- Rituximab: chimeric mAb to CD20 
treat NH lymphoma, 
chronic lymphocytic leukemia 
RA when anti-TNF therapy fails 
off lable MS

Question 13

Use of modified mAbs in tumor diagnosis + treatment

Answer 13

Ibritumomab:
murine mAb against CD20.
It helps chelate Indium and Ytrium and is first FDA approved radioimmunotherapy

mAb images the tumor, Ytrium treats it.