10 - Monoclonal Antibodies Flashcards
list some of the monoclonal antibodies:
what is the gold standard for breast cancer treatment?
gold standard: trastuzumab (Herceptin)
drug names end in -mab
(monoclonal antibodies)
monoclonal antibodies:
define
antibodies that are made by identical immune cells that are all clones of a unique parent cell.
Given almost any substance, it is possible to produce monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance.
how to generate monoclonal antibodies:
Take spleen cells from an immunized animal ; produces an antibody
- myeloma cells are cancer cells (immortal)
- cell fusion; go in tissue culture
- you have to kill off the cells and clear them out? (from the supernatant)
You know the protein, and have to see if they secrete antibody
monoclonal antibodies:
advantages
- immortal
- readily available, continuous supply
- high specificity to a single antigen
- can be used as targeted therapy
monoclonal antibodies:
disadvantages
- high cost of production (v. expensive)
- extent of immunoreactivity –
- highly focused on a single antigen
- as opposed to many antigens - polyclonal antibodies
monoclonal antibodies in cancer chemotherapy:
potential targets
- EGFR (epidermal growth factor receptor)
- VEGFR (Vascular epidermal growth factor)
- Lymphocyte binding proteins
which mechanism involves extracellular domain of transmembrane protein?
CLASSICAL MECHANISM
- Signal binds to the extracellular domain of a transmembrane protein –>
- thereby activating an enzymatic activity of its cytoplasmic domain.
what is the structure of the Epidermal Growth Factor Receptor, and what are the implications of this?
- Structure
- 2 monomers; bind and form dimer –> active dimeric state
- Receptor has extracellular and cytoplasmic domains.
- As such…
- SO if you can prevent EGF binding – you can prevent this pathway from taking place
- Upon EGF binding, receptor converts from inactive monomeric state to an active dimeric state –> in which two receptor polypeptides bind noncovalently.
- The cytoplasmic domains become tyrosine phosphorylated.
- Activated enzymatic functions to catalyze phosphorylation of substrate proteins.
epidermal growth factor receptor INHIBITORS:
mechanism, and drugs
- Mech: Down-regulation
- Binding to epidermal growth factor receptor –> prevents epidermal growth factor (molecule) binding –> preventing cell growth
- Drugs:
- Trastuzumab (Herceptin)
- Cetuximab
- Panitumumab
Trastuzumab (Herceptin):
structure, expression
- Structure:
- A monoclonal antibody against the Her2 protein (the type 2 EGFR), which is overexpressed in 25-30% of breast cancer
- Expression:
- Expression of this protein is associated with decreased survival due to more aggressive disease
Trastuzumab (Herceptin):
mechanism, use, toxicity
- Mech: cell cycle arrest via antibody-mediated cytotoxicity
- Use: Used in Her2+ breast cancer patients in combination with Paclitaxel
- Toxicity:
- Diarrhea and hematologic effects are most common
Trastuzumab (Herceptin):
indications, efficacy
- Indications:
- HER-2/neu-positive tumors in patients with breast cancer
- metastatic gastric or gastroesophageal junction adenocarcinoma
- Efficacy:
- single agent - remission in 15-20% of breast CA pts
- combo chemo - inc. response rates and duration as well as 1 yr survival
Cetuximab:
indications for therapy
- EGFR-positive head and neck squamous cell carcinoma (in combination with radiotherapy or chemotherapy)
- kRas-negative, EGFR-positive metastatic colorectal cancer (in combination with radiotherapy or chemotherapy*)– (for personal therapy)
- Single agent in patients who cannot tolerate certain chemotherapies
Cetuximab:
toxicity
- acute
- infusion reaction
- chronic
- skin rash
- hypomagnesemia - (low magnesium- but Mg is important fro proper cell function)
- fatigue
- interstitial lung disease
Panitumumab:
mech, indications, toxicity
- mech:
- binds to EGFR and inhibits downstream EGFR signaling
- enhances response to chemo and radiotherapy
- indications: colorectal cancer
- toxicity:
- acute - infusion rxn (rarely)
- chronic - skin rash, hypomagnesemia, fatigue, interstitial lung disease
vascular growth factor receptor inhibitors:
mechanism
- mech:
- Antiangiogenic-inhibit growth of blood vessels (angiogenesis) in tumors
angiogenesis:
define
growth of blood vessels
VEGF:
define
vascular endothelial growth factor:
one of the most angiogenic growth factors
(remember: angiogenesis is growth of blood vessels)
What do tumors require, and how does VEGF fit into this?
- Primary and metastatic tumor growth requires INTACT VASCULATURE
- THEREFORE, VEGF-signaling pathway represents an attractive target for chemo
Vascular Growth Factor Receptor Inhibitors:
define
Antiangiogenic-inhibit growth of blood vessels in tumors;
theory: if we knock out “VEGF” – we can “starve the tumor”
Bevacizumab:
mechanism/actions
- Inhibits binding of VEGF-A to VEGFR leading to inhibition of VEGF signaling;
- Inhibits tumor vascular permeability;
- Enhances tumor blood flow and drug delivery
Bevacizumab:
indications and adverse effects
- Indications:
- First- and second-line tx: metastatic colorectal CA alone, or in combo therapy
- non-small cell lung CA,
- gliobastoma multiforme that has progressed after tx
- metastatic kidney CA
- Adverse effects:
- **NEED TO WAIT UNTIL PTS HEAL FROM SURGERY
- Monitor for: hemorrhage, GI perforations, wound healing issues
why do we need to wait until a patient heals after surgery BEFORE STARTING Bevacizumab tx?
- Cutting out the tumor –> disrupts vascular structure
- Vasculature needs to heal first (if not, could cause problems unrelated to CA)
- THEN, the drug inhibits binding of VEGF-A to VEGFR
some examples of lymphocyte binding protein (monoclonal antibodies)?
- Alemtuzumab
- Catumaxomab
- Ofatumumab
- Rituximab
Alemtuzumab:
mechanism
- Binds CD52 found on normal and malignant B and T lymphocytes, NK cells to, monocytes, macrophages, and a small population of granulocytes.
- **NOTE the specificity of this:
- looking at one protein; and using it for tx of B-cell chronic lymphocytic leukemia
Alemtuzumab:
mech, tx, adverse effects
- mech: direct antibody-dependent lysis (tumor and normal cells)
- tx:
- B-cell chronic lymphocytic leukemia (CLL) in patients who have been treated w/ alkylating agents and have failed fludarabine therapy
- adverse effects:
- pts receiving this antibody become lymphopenic and may also become
- **monitor for opportunistic infections and hematologic toxicity
Is Alemtuzumab a primary or secondary agent?
secondary agent and therefore ONLY used for patients that have already failed another drug (cost is an issue)
Catumaxomab:
structure, mechanism, classification, indications
- structure: bi-specific monoclonal antibody –> therefore 2 diff’t targets
- mech:
- targets epithelial cell adhesion molecule (EpCAM) on tumor cells
- targets CD3 protein on T cells
- classified as orphan drug;
- indication: tx abdominal ascites in ovarian and gastric cancers
orphan drugs:
define
- produced against a very rare pathology; not of interest to drug companies (can’t make much money from it)
- special program at NIH helps provide startup money for orphan drugs
Ofatumumab:
target, indication, adverse effects
- target: recognizes CD20 on lymphocytes
- indication:
- patients w/ chronic lymphocytic leukemia (CLL) who are refractory to fludarabine and alemtuzumab (so it’s a secondary tx)
- adverse effects:
- slight risk of hepatitis B virus reactivation
Rituximab:
target, indications, tx, adverse effects
- targets: binds to CD20 molecule on normal and malignant B lymphocytes
- indications:
- pts w/ CD20-positive large B-cell diffuse non-Hodgkin’s lymphoma
- relapsed or refractory low-grade or follicular B-cell non-Hodgkin’s lymphoma as a single agent, OR in combination chemo
- Chronic lymphocytic leukemia in combination w/ chemo
- tx: synergistic w/ chemotherapy
- adverse effects
- **Anemia or neutropenia is an important adverse effect
- hypotension, rash, gastrointestinal disturbance, fever, fatigue
Ziv-aflibercept:
structure, mech
- structure: recombinant fusion protein
- Portions of the extracellular domains of human VEGF receptors (VEGFR) 1 and 2 fused to the Fc portion of the human IgG1 molecule
- mech: serves as soluble receptor to VEGF-A and VEGF-B
- Binding of VEGF ligands prevents their subsequent interactions with the target VEGF receptors
- Results in inhibition of downstream VEGFR signaling (“Takes them out of circulation)
- stops the effect
Ziv-aflibercept:
indications, and adverse effects
- Indications:
- in combination w/ chemo for pts w/ metastatic colorectal cancer that has progressed on oxaliplatin-based chemotherapy
- Adverse effects:
- **Should not be administered until patients heal from surgery
- Pts taking the drug should be monitored for hemorrhage, GI perforations, and wound healing problems
