Biomolecular Therapeutics Flashcards

1
Q

Give some examples of biological therapeutics.

A
  • Vaccines.
  • Antibodies (part of the immune system).
  • Proteins (cytokines, interleukins, colony-stimulating factors).
  • Oligoinucleotides (antisense, gene therapy).
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2
Q

What is angiostatin?

A

This is an internal fragment of plasminogen approximately 38kDa. It inhibits endothelial cell proliferation.

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3
Q

Describe the tolerability and efficacy of angiostatin.

A

It is well tolerated by patients and has high efficacy.

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4
Q

Angiostatin is currently in phase 3 clinical trials. Why might it not have much use in the clinic?

A

It may not have much use in the clinic because of its instability.

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5
Q

What is endostatin?

A

This is a 20kDa fragment of the c-terminus of collagen XVII. It works by blocking mitogen activated protein kinase (MAPK) in endothelial cell proliferation.

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6
Q

How much more potent than angiostatin is endostatin?

A

30x.

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7
Q

What does endostatin have potential use in?

A

Endostatin has potential uses in patients with sarcoma, melanoma, and neuroendocrine tumours.

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8
Q

Why might endostatin not have much use in the clinic?

A

It may not have much use in the clinic based on its instability.

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9
Q

How does avastin (bevacizumab) work?

A

Avastin is an anti-VEGF monoclonal antibody which works by sequestering VEGF, preventing receptor activation. Because it is an antibody it binds very tightly and specifically to VEGF.

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10
Q

What is avastin (bevacizumab) used to treat?

A

It is licensed for the treatment of colorectal, lung, breast (outside the USA), glioblastoma (USA only), kidney, and ovarian cancers.

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11
Q

What are the side effects of avastin (bevacizumab)?

A
  • Heightened bleeding risk.
  • Hypertension.
  • Exacerbation of CAD.
  • Artery diseases.
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12
Q

What is immunotherapy?

A

These are therapies which exploit one’s own immune system for therapeutic benefit.

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13
Q

Give some examples of immunotherapy.

A
  • Vaccination.
  • Therapeutic antibodies/targeting of therapies.
  • Activation of the immune system (NK, LAK, CTL, DC).
  • Bone marrow transplantation.
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14
Q

What are prophylactic vaccines, with respect to cancer treatment?

A

Prophylactic vaccines for cancer are often vaccines that build immunity to viral infections which have been linked to certain cancers. There are also vaccines to bacteria that may be linked to cancer.

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15
Q

Give examples of infections which have vaccines against them and that are linked to cancer.

A
  • HPV (viral).
  • HepB (viral).
  • Helicobacter pylori (bacterial).
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16
Q

Why do viruses have the potential to induce cancer?

A

Viruses have the potential to induce cancer through their method of reproduction. Because viruses reproduce by inserting their genes into the cellular machinery of a host cell, hijacking this machinery to produce more viruses. This can lead to the induction of oncogenes, leading to cancer.

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17
Q

What do therapeutic vaccines for cancer require?

A

Therapeutic vaccines for cancer require the identification of cancer specific immunogenic proteins. These proteins should preferably be on the cell surface to aid targeting; they are usually unique to one cancer.

18
Q

What is the main downside of requiring specific immunogenic proteins for therapeutic cancer vaccines?

A

Because they are unique, they are expensive and can’t be used for multiple different cancers.

19
Q

When making therapeutic cancer vaccines, the difficulty is to find tumor specific antigens rather than tumour associated antigens. What are tumour associated antigens?

A

Antigens associated with changes that the tumour induces.

20
Q

Give some examples of tumour associated antigens?

A
  • EBV.
  • HPV.
  • Glycoproteins.
  • Glycolipids.
  • α-fetoprotein.
21
Q

Explain the idea of vaccines based on cells.

A

This is the idea of modifying normal cells to be active against a certain cancer.

22
Q

How are vaccines based on cells made? How do they work?

A

In this therapy immune cells are taken from the patient, stimulated to identify the cancer, and then put back into the patient for therapeutic effect.

23
Q

Are unwanted immune responses likely with vaccines derived from cells? Why?

A

They are the patient’s own cells so an unwanted immune response (e.g. anaphylaxis) is very unlikely.

24
Q

Explain how classical anticancer therapies are much less targeted than vaccines based on cells.

A

Classical anticancer therapies are much less targeted. For example, alkylating agents which target DNA will target the DNA of all cells which contain DNA (all cells bar erythrocytes); this leads to damage being done to all these cells. Furthermore, this leads to the side effects seen when these agents are used.

25
Q

Give an example of a vaccine based on cells; including its use and how it is made.

A

An example of this is the ‘Provenge’ (Sipulecel-T, APC0815) therapy which is used for hormone refractory metastatic prostate cancer. The patient’s antigen presenting cells (DCs) are extracted and activated (with prostatic acid phosphate found on a very high proportion of prostate cancer cells) and granulocyte-macrophage colony stimulating factor then returned to the patient.

26
Q

Into what two mail classes do therapeutic antibodies fall?

A
  • Antibodies that reply on the host immune system (naked).

* Antibodies conjugated to an anticancer agent (drug, radioactivity, or toxin).

27
Q

How are therapeutic antibodies made?

A

Antibodies are raised to proteins that are uniquely present on the surface of cancer cells, for example CD-52 in leukaemia. They are usually produced from mice and then humanised to ‘hide’ the change made from the immune system – reducing the likelihood of adverse immune reactions.

28
Q

What was the first mAb used for cancer?

A

The first mAb used for cancer was Rituximab (1997) which was raised for CD20 in non-Hodgkin’s lymphoma.

29
Q

In what two ways can naked antibodies act?

A
  • Binding to cell proteins and activating the host immune response, resulting in killing the cell. Recruitment of immune factors.
  • Prevent ligand binding to, or activation of, cell surface receptor to modulate cellular signalling.
30
Q

Give examples of naked antibodies that recruit immune factors.

A
o	Alemutzamab (CD52 in CLL).
o	Rituximab (CD33, NHL).
31
Q

Give examples of naked antibodies that prevent ligand binding or receptor activation.

A
o	Cetuximab (EGFR) prevent ligand binding.
o	Bevacizumab (Avastin) (VEGF-A) prevents activation.
32
Q

What are conjugated antibodies?

A

Conjugated antibodies (ADCs (Antibody-Drug Conjugates)) carry a toxic cargo to the cell.

33
Q

What may conjugated antibodies carry?

A
  • Radioisotopes (radioimmunotherapy) e.g. ibrituomab tiuxetan (90Y).
  • Enzyme prodrug therapy (ADEPT and others).
  • Immunoconstructs – targeted drugs (Brentuximab vedotin – CD30/MauristatinE).
  • Immunoliposomes.
34
Q

How can conjugated antibodies help to reduce toxicity?

A

These conjugated antibodies can help to reduce the toxicity of a drug as the drug is tethered to the antibody so can’t go off to bind to or act at other receptors.

35
Q

What is the main downside to conjugated antibody technology?

A

This cargo needs to be released at the site of action and this can be hard.

36
Q

What is ADEPT therapy?

A

ADEPT stands for antibody direct enzyme prodrug therapy. This is where an enzyme is conjugated to the antibody and this conjugate is administered with a prodrug. The enzyme is taken to the desired site of action and here it metabolises the prodrug into active drug, then it has its effect.

37
Q

What is the benefit of ADEPT therapy?

A

The benefits of this is that the prodrug has little toxicity and adverse effects. The active drug only works at the desired site of action, further reducing the likelihood of adverse effects.

38
Q

Explain the use of growth factors in cancer therapy.

A
These include colony stimulating factors (e.g. granulocyte colony stimulating factor, G-CSF) and they are often used to combat side effects of other therapies.
Examples include:
•	Bone marrow (Lenogastrim, Filgrastim).
•	Erythrocytes (erythropoietin).
•	Platelets (interleukin 11).
39
Q

Give examples of growth interleukins and interferons used in cancer treatment.

A

• IL-2 – growth and activity of immune cells (e.g. lymphocytes).
o Melanoma, kidney.
• INFα – stimulate immune system and slow cancer growth.

40
Q

Explain how viral therapies can be used to combat cancer.

A

With this technology, a virus is raised that is selective for cancer cells; this can be via invasion or a virus that only replicated in cancer cells. One should choose a virus that causes lysis (adenovirus, vaccinia, herpes). It may also be possible to produce viruses to produce anticancer proteins (e.g. GM-CSF).