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Therapeutics > Exam 1 lecture 6 > Flashcards

Exam 1 lecture 6 Flashcards

1
Q

What is the first attempted immunotherapy? how did it work?

A

Coleys toxin. Promotes non specific inflammatory response

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2
Q

What are the types of cells that show adaptive immunity? WHich ones produce antibodies?

A

T cells, B cells, Plasma cells

B cells promote antibodies

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3
Q

Why do antibodies produced by mice need to be changed

A

They need to be changed to mimic a human orotein or they will be recognized as foreign by the patients immune system

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4
Q

Explain the nomenclature of antibodies with exapmles

A

-o = mice

-Xi= chimeric (cetuximab)

-Zu= humanized (trastuzumab)

-U= fully humanized (ramucirumab)

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5
Q

What are the two ways antibody binding to cell surface receptor affect the cell? Compare with Kinase inhibitor

A
  1. Binding of large proteins to cell surface receptors will inhibit function
  2. It will also activate complement (ADCC)

Antibody activates complement AND blocks binding. Kinase only does one (blocks binding)

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6
Q

How does the amount of HER2 in a cell matter

A

Normal amount of HER2 send signals telling cells to grow and divide

Too many HER2 receptors send more signals, causing cells to grow too quickly (HER2 overexpressed in 30% of all breast cancers)

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7
Q

Trastuzumab (herceptin) MOA, indication and toxicity

A

Specific for HER2 and immune response to antibody is reduced by human framework of IgG

Herception binds to receptor and induces antibody dependent cytotoxicity. Also induces receptor internalization and degradation.

primary indication- Tx of breast cancers that overexpress HER2

toxicity- Risk of hypersensitivity
FLu like symptoms
Cardiomyopathy

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8
Q

MOA of pertuzumab?

A

Also binds HER2, but does it differently to trastuzumab.

Pertuzumab binds to HER2 and inhibits dimerization

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9
Q

What drug is pertuzumab used in combination with?

A

Trastuzumab. Due to different mechanisms of effecting HER2.

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10
Q

Cetuximab MOA, indication and toxicity

A

MOA- EGFR antibody competitive inhibitor that inhibits binding of EGF and TGF-alpha. It also blocks phosphorylation and activation of kinases. These lead to inhibition of cell growth and induction of apoptosis.

Primary indication- Colorectal and head and neck cancer

Toxicity- WARNING!!! SEVERE infusion reaction in 3% of patients. usually 1st dose.
Rash
Fever

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11
Q

Why would we expect the toxicities associated with cetuximab

A

EGFR is important for skin maintenance. This forms rash. Rash=better prognosis

Infusion rxn comes from non specific immune response to antibodies

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12
Q

What are the two antibodies that target EGFR?

A

Cetuxumab
panitumab

No infusion side effect with panitumumab

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13
Q

Panitumab MOA, toxicity, indication

A

MOA- competitively inhibits EGF and TGF-a. This blocks phosphorylation of kinases and leads to inhibition of cell growth and apoptosis

side effects- skin rash, diarrhea
indication- treatment of colorectal cancer

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14
Q

MOA of bevacizumab? Indication?

A

Specific for VEGF

Binds to VEGF and blocks its interaction with endothelial receptors.

Blocks endothelial cell proliferation

Used in combo with 5-FU based chemo for 1st line tx of colorectal cancer

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15
Q

Is there efficacy of bevacizumab as single agent

A

No

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16
Q

Difference between bevacizumab and ramucirumab

A

Bevacizumab binds ligand, ramucirumab binds receptor

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17
Q

Explain the 2 tiered targeting effect of antibody therapy compared to small molecule kinase inhibitor

A
  1. bind to target and inhibit function
  2. activate ADCC (complement).

Complement leads to different outcome compared to small molecule

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18
Q

describe why combining uses for pertuzumab and trastuzumab both defy and comply wuth general rules

A

against- shared target= shared toxicity
For- Different binding sites of HER2, different mechanism of inhibition, enhanced ADCC

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19
Q

What is CD 20 and what does it do?

A

CD20 works with B cell receptor to drive proliferation of B cells

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20
Q

What happens when antibody binds to CD 20

A

antibody binding to CD20 inhibits B cell proliferation and induces antibody dependent cytotoxicity

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21
Q

What are the drugs that target CD 20

A

Rituximab
ofatumumab

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22
Q

Rituximab MOA

A

Binds Cd 20 .

CD 20 is expressed on normal B cells, but also90% of B cell non-hodgkins lymphoma cells

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23
Q

Where are CD-38 found

A

Plasma cells

24
Q

Name CD 38 antibodies

A

Daratumumab

25
Q

What cells do antibodies for CD 38 like daratumumab eliminate?

A

Multiple myeloma cells (via ADCC or CDC)
Also eliminated NK cells

26
Q

Name an antibody drug conjugate

A

Ado-trastuzumab emtasine (TDM1)

27
Q

MOA of TDM1

A

Trastuzumab binds to HER/Neu receptor and leads to usual herceptin response.

Emtasine enters cell and inhibits microtubule assemble.

28
Q

What happens to emtasine toxicity in TDM1

A

Emtasine toxicity significantly reduced due to selectivity to HER2

29
Q

toxicity of TDM1

A

Adverse effects of trastuzumab
hepatotoxicity

30
Q

Explain central tolerance

A

Negative selection of T cells that bind to “self” peptides.

If cells have no interaction with self or too tightly to self leads to apoptosis

31
Q

explain peripheral tolerance

A

Self reactive T cells that escape the thymus into peripheral tissues are inactivated to an unresponsive state

32
Q

How are T cells activated

A

T cell encounters antigen in combination with MHC

If T cell recognizes antigen it will be activated. A cytolytic T cell will kill that cell and proliferate creating a population of antigen specific T cells

Once infection clears they turn to memory cells.

33
Q

What is BiTe (Bi-specific T cell engager)

A

Binds simultaneously to CD 19 on B cell and on CD-3 which is present on T cell and forces them together

34
Q

Name the BiTe drugs

A

Blinatumomab
Mosenutuzumab
Teclistamab
Taquetamab

35
Q

MOA of blinatumomab

A

BiTe that targets T cells present on cancer.

Binds CD-3 to physically bring an activated T cell into proximity with CD 19 expressed on B cells

36
Q

Mosenutzumab MOA

A

BiTe targeting CD3 and CD20 on non hodgkins lymphoma

37
Q

side effects of mosenutzumab

A

Cytokine release syndrome

38
Q

Teclistamab MOA

A

Targets BCMA (b cell maturation antigen) on multiple myeloma

39
Q

Taquetamab MOA

A

BiTe on GPCR Targeting multiple myeloma cells

40
Q

What do CTLA-4 and PD-1 do

A

They act as brakes or checkpoints on immune systems.

41
Q

What happens when we block CTLA 4 and PD-1

A

they can reactivate T cells

42
Q

What are CTLs

A

cytotoxic T lymphocytes. They have the capacity to recognize and destroy malignant tumor

43
Q

Ipilimumab MOA

A

Binds CTLA-4 receptor and reverse CTL inhibition

44
Q

How is CTL inhibited

A

Tumor cell antigen recognized by dendritic cells which present antigens to CTLs.

dendrtitic cells deliver inhibitory signal to CTLs via CTLA-4 receptor

45
Q

pembrolizumab MOA

A

monoclonal antibody that binds PD-1 receptor and blocks its interaction with PDL-1 and 2

46
Q

Where is PD-1 expressed?

A

T cells

47
Q

Where is PD-L1 expressed?

A

Macrophages and tumor cells

48
Q

What happens when CTLA-4 and PD-1 are blocked

A

CTLA-4 and PD-1 blockade prevents inhibitory signal within T cells leading to enhanced tumor cell killing

49
Q

Atezolizumab MOA? Who would be excluded?

A

Binds PD-L1 and blocks interaction with PD-1

people with autoimmune disease and medical conditions requiring immunosuppressions are excluded

50
Q

sipuleucel (provenge) MOA? Indication?

A

Not a drug- more like a process.
Activates APCs collected from patient and reinfused into patient

used for metastaic prostate cancer

51
Q

CAR T cell therapy MOA

A

Programming T cells by genetically entering receptors that bind cancer

52
Q

Which antibody is effective against metastatic melanoma and targets CTLA4

A

Ipilimumab

53
Q

Which protein is used as a cancer biomarker test to determine eligibility for treatment of NSCLC with pemrolizumab

A

PDL-1

54
Q

Common target for CAR-T

A

CD-19

55
Q

MOA of bispecific T cell enzymes

A

They bring T cells and cancer cells in close proximity to facilitate T cell mediated cytotoxicity

Therapeutics (15 decks)

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