Targeted Therapy Flashcards
What does “MAB” mean in the spelling of a medication?
Monoclonal antibody; target will be a cell surface receptor that activates a signaling cascade leading to proliferation
Drug names that end in “ib” indicate what?
The drug is an inhibitor agent of tyrosine kinase receptors
Trastuzumab
A monoclonal antibody drug
Target: Binds to and down-regulates HER-2 receptor
Effect: Cell cycle arrest
Cancer: Breast cancer
Which drug binds to and down-regulates the HER-2 receptor?
Trastuzumab
Which drug prevents dimerization of the HER-2 and HER-3 receptors, thereby preventing HER-2 from phosphorylation HER-3? What cascade does it prevent?
Pertuzumab
PI3K
Pertuzumab
Monoclonal antibody drug
Target: HER-2 and HER-3
Effect: Recall that HER-2 dimerizes with and phosphorylates HER-3, and they then promote the PI3K cascade. Pertuzumab prevents formation of the heterodimer.
Cancer: Breast cancer
T-DM1
These drug types contain in their structure both an antibody and a cytotoxic agent. In Sweatman’s example, they are binding the EGFR.
1) Antibody action finds the receptor
2) Delivery of a cytotoxic agent to the tumor target, thus minimizing distribution of the native drug throughout the body.
Ipilimumab
A monoclonal antibody drug
Target: Binds CTLA-4 so that the tumor cell cannot send its B7 to bind. Normally, if B7 binds CTLA-4, the T-cell gets the message that it need to activate and proliferate. Because this antibody drug takes up the CTLA-4 binding site, the only other one open for B7 is CD28, which activates the T-cell, perhaps giving it a chance to attack tumor cells.
Cancer: Melanoma
Interesting note: This drug was the first to utilize active immunotherapy, as opposed to the suppression tactic.
Which drug binds the CTLA-4 receptor on T-cells to prevent B7 (CD80/86) from binding?
Ipilimumab
Rituximab
A monoclonal antibody drug
Target: Binds to the surface of the transmembrane protein CD20, which is found on precursor and mature B-cells. Recall that CD20 regulates early steps in the activation process for cell cycle initiation and differentiation.
Effect: Binding of the antibody drug produces rapid and sustained depletion of B-cells, lasting for several months. ADCC, apoptosis, and CDC
Cancer: Chronic lymphocytic leukemia and non-Hodgkin’s lymphoma
VEGFR pathway normally activated with whom and when?
This pathway is activated in large, solid tumors that are beginning to outgrow their vascular supply. Because the cancer needs increased blood supply to spread, the VEGFR is a great target for monoclonal antibody drugs.
Hypoxia inducible factor-1 (HIF-1) in times of oxygen deprivation
In times of oxygen deprivation, VHL (Von Hippel Lindau) allows this molecule to translocate to the nucleus to promote up-regulation and expression of VEGF and PDGF, which then promotes angiogenesis.
The ultimate result is metastatic tumor spread, proliferation, and survival.
HIF-1 in times of plentiful oxygen
When oxygen levels are sufficient, any HIF-1 produced is sent by VHL (Von Hippel Lindau) to the 26s proteasome complex for degradation.
General Characteristics of MABs
Route of admin, immunoglobulin on which they’re based, general target
Administered by injection
Large protein structures
Based on IgG
Traditionally target classical proliferative cell surface targets
Ipilimumab, which you’ll recall targets CTLA-4, is the first drug to take the approach of immune system activation.
Adverse effects of monoclonal antibodies
Recall that we’re targeting mammalian targets, and that these targets, while OVERexpressed in tumor cells, are regularly expressed in non-tumor cells; thus, we see things like:
1) Cardiovascular problems, including CHF and HTN
2) Depletion of cell populations in blood where target is expressed in component of this tissue
3) Infusion related reactions, like anaphylaxis, angioedema, and pulmonary toxicity. To mitigate this issue, give antihistamines and/or corticosteroids.
Cetuximab
A monoclonal antibody drug
Target: EGFR-1, HER-1
Effect: Apoptosis, ADCC of cell
Panitumumab
A monoclonal antibody drug
Target: EGFR-1, HER-1
Effect: Apoptosis, ADCC
Which two drugs target EGFR-1 , HER-1? Their killing mechanisms?
Cetuximab and Panitumumab
ADCC and apoptosis
Bevacizumab
Target: VEGF
Effect: Prevents angiogenesis and neovascularization
Which drug targets VEGF to prevent angiogenesis by tumor cells?
Bevacizumab