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Year 3 - Biotechnology > 9 - MAb in Cancer > Flashcards

9 - MAb in Cancer Flashcards

1
Q

Classes of monoclonal antibodies for cancer

A
  • CD antigens (alemtuzumab)
  • Vascular endothelial growth factor inhibitors (bevacizumab)
  • Epidermal growth factor receptor inhibitors (trastuzumab)
  • Immune checkpoint inhibitors (nivolumab)
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2
Q

Describe the general mechanism of cancer

A
  1. Multistep carcinogenesis model
    - Discovery of oncogene and tumour suppressor gene (c-myc, c-fos; Rb, p53)
    - Two-hit hypothesis (Knudson hypothesis)
    - - Activator of pro-oncogene
    - - Inactivation of tumour suppressor gene
  2. Multiple-hit hypothesis aka hallmarks of cancer (from 6 hallmarks to 10 hallmarks)
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3
Q

Mechanisms of antibodies in cancer

A
  1. Direct tumour cell killing
    - Receptor antagonist, receptor agonist
    - Conjugated antibody
    - Antibody + enzyme bind to tumour cell
  2. Immune-mediated tumour cell killing
    - Phagocytosis, complement, ADCC, cross-presentation and T cell activation
  3. Vascular and stromal cell ablation
    - Antibodies inhibits growth of blood vessel or growth of stroma cell (present in tumour)
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4
Q

Target and indication for trastuzumab

A
  • Target = ERBB2
  • Indication = ERBB-2+ breast cancer, as a single agent or in combo w/ chemo for adjuvant or palliative tx; ERBB-2+ gastric or gastroesophageal junction carcinoma as first-line tx in combo w/ cisplatin & capecitabine or 5-fluorouracil
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5
Q

Target and indication for bevacizumab

A
  • Target = VEGF
  • Indication = first-line or second-line tx of metastatic colon cancer in combo w/ 5-fluorouracil-based chemo; first-line tx of advanced NSCLC in combo w/ carboplatin and paclitaxel in px who haven’t yet received chemo; in conjunction w/ IFNs to treat metastatic kidney cancer
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6
Q

Target and indication for cetuximab

A
  • Target = EGFR

- Indication = in combo w/ radiation for initial tx of locally or regionally advanced SCCHN

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7
Q

Target and indication for panitumumab

A
  • Target = EGFR

- Indication = single agent for tx of pretreated EGFR-expressing metastatic colorectal carcinoma

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8
Q

Target and indication for alemtuzumab

A
  • Target = CD52

- Indication = single agent for tx of B cell chronic lymphocytic leukemia

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9
Q

Purpose of MAb and how are they organized?

A
  • Purpose = can be used to improve overall survival, increase time to progression, and delay time to recurrence of many oncologic diseases
  • Organized based on their target:
    • CD cell surface antigens (CD20, CD52)
    • Vascular endothelial growth factor (VEGF) receptor
    • Epidermal growth factor receptor (EGFR, HER2)
    • Immune checkpoint (CTLA-4, PD-1)
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10
Q

Classes of Mab – CD antigens

A
  • Cluster of differentiation (cluster of designation), often called CD, is a protocol used for the identification and investigation of cell surface molecules present on leukocytes
  • CD molecules can act in numerous ways, often acting as receptors or ligands important to the cell
    • Signal cascade is usually initiated, altering the behaviour of the cell
  • Some CD proteins don’t play a role in cell signalling, but have other functions, such as cell adhesion
  • Around 250 different proteins
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11
Q

Alemtuzumab – target, function, and use

A
  • Unconjugated, humanized, IgG1 kappa monoclonal Ab directed against the 21-28 kDa cell surface glycoprotein CD52
  • CD52 is not shed or internalized so making it an excellent therapeutic target
  • CD52 is highly expressed in certain cancer cells (chronic lymphocytic leukemia, CLL)
  • Compound exerts its effect by binding to CD52 antigenic sites and stimulating cross-linking by Abs
    • Complement dependent cytotoxicity (CDC)
    • Direct cellular apoptosis via NK activity
  • As a single agent for the tx of B cell chronic lymphocytic leukemia
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12
Q

Alemtuzumab – dosage and administration

A
  • Administered according to a dose-escalation schedule
  • Single doses of > 30 mg and weekly doses > 90 mg are not recommended, due to risk of severe pancytopenia
  • Should be infused through IV line that doesn’t contain any other drug substances
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13
Q

Classes of Mab – vascular endothelial growth factor inhibitors

A
  • Folkman theory -> development of new blood vessels (angiogenesis) must occur for tumour growth beyond 1-2 mm^3
  • As tumours enlarge, the centers become hypoxic and stimulate angiogenic growth factors
  • VEGF is thought to be one of the most potent growth factors and has been shown to induce neovascularization for malignant cells in an autocrine fashion
  • Levels of VEGF in blood have been correlated w/ poor prognosis, disease recurrence, and metastases in a variety of neoplasm
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14
Q

Steps of angiogenesis in cancer formation and metastasis

A
  1. Premalignant stage = avascular tumour
  2. Malignant tumour -> angiogenic switch
  3. Tumour growth – vascularized tumour
  4. Vascular invasion -> tumour cell intravasation
  5. Dormant micrometastasis -> seeding in distant organs
  6. Overt metastasis -> secondary angiogenesis
    Angiogenesis plays a role in tumour progression at stages 2, 3, 4, and 6
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15
Q

Bevacizumab – target and function

A
  • Currently the only FDA approved VEGF inhibitor available
  • Humanized MAb that consists of a normal human IgG and the VEGF binding residues from a murine neutralizing Ab
  • Designed to block a protein called vascular endothelial growth factor (VEGF) which promote growth of blood vessels
    • Once a tumour reaches a critical size (0.5-2 mm) more blood vessels are required for more nutrients and oxygen to grow
  • Unlike chemo that attacks the cancer cells, bevacizumab starves tumour cells (anti-angiogenesis) from growth
  • Has demonstrated both cytostatic and cytotoxic effects
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16
Q

Bevacizumab indications

A
  • Metastatic colon cancer -> first-line and second-line tx in conjunction w/ 5-fluorouracil-based chemo
  • Non-small cell lung cancer -> first-line tx of advanced NSCLC in combo w/ carboplatin and paclitaxel in px who haven’t received chemo
  • Glioblastoma -> single agent in px whose tumour has progressed after initial tx
  • Kidney cancer -> conjunction w/ IFNs
17
Q

Bevacizumab dosage and administration; most common SE

A
  • Preparation w/ NS for infusion
  • Dextrose solutions should never be used as diluents or administrated concomitantly
  • Infusion time can be 90, 60, or 30 mins
  • Most common SE = back pain, proteinuria, dry skin, headache
18
Q

Epithelial growth factor receptor inhibitors

A
  • EGFR/ HER-1 or EGFR 2/HER-2 are transmembrane glycoproteins constitutively expressed in many normal epithelial tissues including skin and hair follicle
  • EGFR and HER are members of Erb family of receptors that play a role in normal cell growth and differentiation
  • HER-2 protein overexpression can occur in up to 30% of px w/ metastatic breast cancer and is often associated w/ more aggressive disease, a faster relapse time, and overall poor prognosis
  • Trastuzumab (Herceptin) is a recombinant DNA-derived humanized MAb that selectively binds to the extracellular domain of the human HER-2 receptor w/ high affinity
19
Q

Function of EGFR inhibitors

A
  • Inhibit angiogenesis
  • Inhibit cell migration and invasion
  • Inhibit cell proliferation
  • Enhance apoptosis
20
Q

Trastuzumab – indication

A
  • Indicated for HEB2 overexpressing breast cancer
    • Single agent for tx of px w/ HER-2 over-expressing metastatic breast cancer and who had previously been treated w/ chemo
    • In combo w/ paclitaxel in px w/ HER-2 over-expressing metastatic breast cancer and hadn’t received any prior chemo
  • Herceptin indicated for HER-2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in combo w/ cisplatin and capecitabine or 5-fluorouracil for those who haven’t received prior tx
21
Q

How is HER2 positive breast cancer diagnosed?

A
  1. Immunohistochemistry (IHC) test
    - - Most commonly used test
    - - Determines amount of HER2+ receptor protein on cancer cell surfaces
    - - Scale of 0 to 3+ is used => 0 or 1+ = HER2-; 2+ = should be retested using the FISH test; 3+ = HER2+
  2. Fluorescence in situ hybridization (FISH) test
    - - Most accurate test
    - - Determines if the tumour cells have a normal number of HER2 genes (compares # of HER2 genes w/ the # of normal genes in the tumour cells)
    - - The tumour is HER2+ if there are 2 or more HER2 genes for every normal gene in the cells
22
Q

Trastuzumab dosage

A
  • Initial dose = 4 mg/kg over 90 min infusion
  • Weekly maintenance dose = 2 mg/kg over 30 mins
  • Tx duration = indefinitely (or until disease progression) in metastatic breast cancer; 52 weeks as adjuvant tx
23
Q

Trastuzumab safety issues

A
  • Heart problems – CHF, reduced heart function w/ or w/o sx, highest in people w/ both Herceptin and anthracycline
  • Infusion reactions -> fever and chills, N/V, headache, dizziness, SOB
24
Q

What are the 3 sites for therapeutic intervention w/ immune checkpoint inhibitors?

A
  1. Promoting antigen presentation functions of dendritic cells
  2. Promoting production of protective T cell responses
  3. Overcoming immunosuppression in the tumour bed
25
Q

Immune checkpoint inhibitors – function; describe the normal immune response vs. tumour immune evasion

A
  • Immune checkpoint consists of several proteins on cell surface of both cytotoxic T lymphocytes and cancer cells
  • These proteins can either stimulate or inhibit cytotoxic T lymphocytes
  • Cancer cells are able to express proteins that inhibit cytotoxic T lymphocyte
  • PD-1 is a protein on the surface of activated T cells
    • PD-L1 or PD-L2 bind to PD-1, which inactivates the T cell
  • PD-1 receptor = nivolumab, pembrolizumab, pidilizumab
  • PD-L1 ligand = atezolizumab
  • Normal immune response = T-cell activation and tumour attack
  • Tumour immune evasion = T-cell inactivation through the PD-1 immune checkpoint
  • Normal immune response restored = T-cell reactivation and decreased tumour growth through PD-1 immune checkpoint inhibition; while having an effect on the tumour, this could also affect normal cells
26
Q

Nivolumab – function

A
  • A human IgG4 anti-PD-1 MAb
  • Doesn’t exert direct effect on tumour by cytotoxic or tumour growth inhibition
  • Blocks a negative regulator of T-cell activation and response thus allowing the immune system to attack the tumour
  • Normally, PD-L1 and PD-1 interaction is one way that the body regulates the immune system to avoid an overreaction
  • Many cancer cells make PD-L1 which inhibits T cells from attacking the tumour
27
Q

Nivolumab dosage, administration, and SE

A
  • IV infusion over 60 mins
  • Indicated for unresectable or metastatic melanoma, metastatic non-small cell lung cancer, and advanced renal cell carcinoma
    • Can be used w/ ipilimumab for melanoma
  • Immune-mediated diseases -> pneumonitis, colitis, hepatitis, skin adverse reactions
  • Serious SE = pneumonia, PE, dyspnea, pleural effusion
  • Common SE = fatigue, MSK pain, cough, dyspnea, decreased appetite

Year 3 - Biotechnology (11 decks)

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