Pharmacology Iii - Biological Targeted Therapy

Front 1

Cancer therapy is divided into these 4 main subgroups

Back 1

Cytotoxic Chemotherapy
Immune Therapy
Hormone Therapy
Biological Target Therapy

Front 2

Biological Target Therapy is...

Back 2

A type of treatment that uses drugs or other substances to identify or attack specific cells through biological recognition

Front 3

How does biological targeted therapy work?

Back 3

The agent targets a tumor-specific antigen that is expressed at high levels in the tumor and low levels in normal tissue.

The pathologist analyzes the tumor for specific antigens. For example, breast cancer can be analyzed for the Herceptin (HER) - 2 marker which occurs in 25% of patients. Those with the marker are eligible for therapy.

Front 4

How is this therapy normal used?

What is a benefit of this therapy?

Back 4

With chemo or radiation therapy

It has a better toxicity profile than cytotoxic chemotherapy

Front 5

Describe the different types of targeted therapy.

Back 5

Targeted Therapy -->
Antibody - Unconjugated antibody and Conjugated antibody radioactive
Small Molecular Inhibitor- TKI (ATP mimetics) and 26S proteosome inhibitor

Front 6

On an antibody, what is the function of the tip of the Fab portion?

Back 6

To recognize the antigen

Front 7

Describe the different antibody types from mouse to human and the differences between them.

Back 7

Mouse = 100% mouse
Chimeric = 70% human
Humanized = 90% human
Human = 100% human

As the antibody gets more "human", there is a decreased chance of immunological reaction and a greater risk in the loss of specificity

Front 8

Explain how these monoclonal antibodies are named.

Back 8

Mouse = O
Chimeric = xi
Humanized = zu
Human = u

Chimeric-humanized = xizu

Front 9

Cetuximab is therefore what type of antibody?

Back 9

Human Chimeric monoclonal antibody

Front 10

What are the 4 main modes of action of therapeutic antibody?

Back 10

Signaling Blockade
Antibody dependent cell mediated cytotoxicity
Complement dependent cytotoxicity
Delivery of payload

Front 11

Describe how Signaling Inhibition works.

Back 11

Normally, a ligand will bind to a receptor and dimerize leading to activation and downstream signaling.

In signaling inhibition, a Mab will bind directly to the receptor or to the ligand binding domain or cause internalization of the receptor.

Front 12

Describe how Antibody - dependent cell-mediated cytotoxicity works.

Back 12

The target cell is coated with antibodies and lysed or phagocytosed by macrophages or Natural Killer cells.

l

Front 13

Which portion of the antibody binds to the antigen? Effector cell?

Which antibody type holds the greatest effector cell function?

Back 13

Fab portion of antibody - recognizes antigen
Fc portion - recognizes immune system effector cell

IgG1

Front 14

How does Complement-dependent cytotoxicity work?

Back 14

Antibody-Antigen binding initiates the complement cascade. Chemotactic factors are released from effector cells that result in the formation of a membrane attack complex and the creation of large pores in the cell.

This is thought to have minimal effect in terms of biological targeted therapy.

Front 15

Describe how Delivery of Payload works.

Back 15

In this scenario, antibodies aren't expected to elicit any biological effect other than to "carry" (be conjugated to) a radioactive or therapeutic molecule. The conjugated molecule then carries out therapeutic action.

Front 16

Any type of tumor component can be a target for Mab therapy! The Mab is injected. It can bind to the surface of endothelial cells, secreted proteins, circulatory cells (blood cells), epithelial cells and tumor stroma inside the tumor parenchyma.

Which are these are currently clinically available?

Back 16

Mab's that bind to secreted proteins, circulatory cells and epithelial cells
However endothelial and stroma cell therapy is showing good efficacy in clinical trials.

Front 17

One of the major advantages of Mab's are that they have less cytotoxicity than chemotherapy. What are some of the drawbacks? (3)

Back 17

Hypersensitivity reaction (minimized by human antibody)
Limited route of injection -- IV
Long half life

Front 18

Name the two types of small molecular inhibitor.

These are much smaller than Mab's and therefore can enter and target many parts of a cell.

Back 18

Tyrosine Kinase Inhibitors - small molecules bind to the ATP binding pocket at the activation loop of target kinases inhibiting their kinase activity (ATP Mimetics)

26S Proteosome Inhibitor - Inhibition of 26S Proteosome activity.

Front 19

So the size of small molecular inhibitors vs Mab's is a big difference, as well as the site of action. Where do Mab's work in comparison to small molecular inhibitors?

Back 19

Mab's - surface antigens, secreted proteins

Small Molecular inhibitors work intracellularly at a number of potential sites.

Front 20

What are the mechanism's of action of both Mab's and Small Molecular Inhibitors?

Back 20

Mab's - ADCC, CDC, Signaling Blockade

Small Molecular Inhibitors - Inhibition of ATP binding
Inhibition of proteosome activity

Front 21

What are the differences between Mab's and SMIs in terms of route of administration and access to the BBB?

Back 21

Mab's are limited to IV Injection and cannot cross the BBB

SMI's can be given IV or PO and may or may not be able to cross the BBB.

Front 22

What is the difference in half life and dose rate?

Back 22

Mab's have a half life of weeks and are administered once/week

SMI's have a half life of days and are administered once/day

Front 23

What is the difference in specificity and cross reactivity?

Back 23

Mab's are more specific and less cross reactive

Mab's also have had a greater success rate in terms of FDA approval

Front 24

What type of agent is Bortezomib?
How does it work?

Back 24

A Small Molecular Inhibitor

Inhibits the 26S Proteosome leading to inhibtion of degradation of ubiquitinated tumor suppressor proteins and activates the NFkB pathway
Proteosome function is crucial to the degradation of ubiquitinated proteins and without this function cell death occurs quickly.

Front 25

What is Bortezomib indicated for?

Back 25

Advanced Multiple Myeloma and Relapsed Mantle cell Myeloma

Front 26

What are the side effects of Bortezomib?

Back 26

Thrombocytopenia, Neutropenia, Anemia

It is highly metabolized in the liver and has a half life of 50-100 hours.

Front 27

Describe the significance of NFkB in Bortezimab.

Back 27

Bortezimab inhibits the degradation of IkB, which keeps the NFkB pathway activated. When the NFkB pathway is activated, there is a decrease in the number of anti-apoptotic factors released. This is bad for a cancer cell.