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Y1 - Pharm > 10 - Monoclonal Antibodies > Flashcards

10 - Monoclonal Antibodies Flashcards

1
Q

list some of the monoclonal antibodies:

what is the gold standard for breast cancer treatment?

A

gold standard: trastuzumab (Herceptin)

drug names end in -mab

(monoclonal antibodies)

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2
Q

monoclonal antibodies:

define

A

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.

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3
Q

how to generate monoclonal antibodies:

A

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

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4
Q

monoclonal antibodies:

advantages

A
  • immortal
  • readily available, continuous supply
  • high specificity to a single antigen
  • can be used as targeted therapy
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5
Q

monoclonal antibodies:

disadvantages

A
  • high cost of production (v. expensive)
  • extent of immunoreactivity –
    • highly focused on a single antigen
    • as opposed to many antigens - polyclonal antibodies
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6
Q

monoclonal antibodies in cancer chemotherapy:

potential targets

A
  • EGFR (epidermal growth factor receptor)
  • VEGFR (Vascular epidermal growth factor)
  • Lymphocyte binding proteins
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7
Q

which mechanism involves extracellular domain of transmembrane protein?

A

CLASSICAL MECHANISM

  • Signal binds to the extracellular domain of a transmembrane protein –>
  • thereby activating an enzymatic activity of its cytoplasmic domain.
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8
Q

what is the structure of the Epidermal Growth Factor Receptor, and what are the implications of this?

A
  • 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.
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9
Q

epidermal growth factor receptor INHIBITORS:

mechanism, and drugs

A
  • Mech: Down-regulation
    • Binding to epidermal growth factor receptor –> prevents epidermal growth factor (molecule) binding –> preventing cell growth
  • Drugs:
    • Trastuzumab (Herceptin)
    • Cetuximab
    • Panitumumab
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10
Q

Trastuzumab (Herceptin):

structure, expression

A
  • 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
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11
Q

Trastuzumab (Herceptin):

mechanism, use, toxicity

A
  • 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
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12
Q

Trastuzumab (Herceptin):

indications, efficacy

A
  • 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
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13
Q

Cetuximab:

indications for therapy

A
  • 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
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14
Q

Cetuximab:

toxicity

A
  • acute
    • infusion reaction
  • chronic
    • skin rash
    • hypomagnesemia - (low magnesium- but Mg is important fro proper cell function)
    • fatigue
    • interstitial lung disease
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15
Q

Panitumumab:

mech, indications, toxicity

A
  • 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
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16
Q

vascular growth factor receptor inhibitors:

mechanism

A
  • mech:
    • Antiangiogenic-inhibit growth of blood vessels (angiogenesis) in tumors
17
Q

angiogenesis:

define

A

growth of blood vessels

18
Q

VEGF:

define

A

vascular endothelial growth factor:

one of the most angiogenic growth factors

(remember: angiogenesis is growth of blood vessels)

19
Q

What do tumors require, and how does VEGF fit into this?

A
  • Primary and metastatic tumor growth requires INTACT VASCULATURE
  • THEREFORE, VEGF-signaling pathway represents an attractive target for chemo
20
Q

Vascular Growth Factor Receptor Inhibitors:

define

A

Antiangiogenic-inhibit growth of blood vessels in tumors;

theory: if we knock out “VEGF” – we can “starve the tumor”

21
Q

Bevacizumab:

mechanism/actions

A
  • Inhibits binding of VEGF-A to VEGFR leading to inhibition of VEGF signaling;
  • Inhibits tumor vascular permeability;
  • Enhances tumor blood flow and drug delivery
22
Q

Bevacizumab:

indications and adverse effects

A
  • 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
23
Q

why do we need to wait until a patient heals after surgery BEFORE STARTING Bevacizumab tx?

A
  1. Cutting out the tumor –> disrupts vascular structure
  2. Vasculature needs to heal first (if not, could cause problems unrelated to CA)
  3. THEN, the drug inhibits binding of VEGF-A to VEGFR
24
Q

some examples of lymphocyte binding protein (monoclonal antibodies)?

A
  • Alemtuzumab
  • Catumaxomab
  • Ofatumumab
  • Rituximab
25
Q

Alemtuzumab:

mechanism

A
  • 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
26
Q

Alemtuzumab:

mech, tx, adverse effects

A
  • 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
27
Q

Is Alemtuzumab a primary or secondary agent?

A

secondary agent and therefore ONLY used for patients that have already failed another drug (cost is an issue)

28
Q

Catumaxomab:

structure, mechanism, classification, indications

A
  • 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
29
Q

orphan drugs:

define

A
  • 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
30
Q

Ofatumumab:

target, indication, adverse effects

A
  • 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
31
Q

Rituximab:

target, indications, tx, adverse effects

A
  • 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
32
Q

Ziv-aflibercept:

structure, mech

A
  • 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
33
Q

Ziv-aflibercept:

indications, and adverse effects

A
  • 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

Y1 - Pharm (12 decks)

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