- 30-35% mouse - more side effects

- 10% mouse - Fewer side effects - hyper variable region

- Fully human - Fewest side effects

Therapeutic proteins Flashcards by emily lawrence

Advantages of monoclonal antibodies

Long half-life
Specificity
Large # of potential targets.
Help for diagnostics and design disease process

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Disadvantages of monoclonal antibodies

Hypersensitivity reactions (esp. human-mouse antibody reactions)
Infusion reactions/Cytokine release syndrome
Infections (esp. TB reactivation)
Effects on immunizations, cancer, fertility/pregnancy, birth defects???

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Major disadvantages of cytokine therapy

Extremely short half-lives
Complicated nature of biological response
Extremely potent with potential for unpredicatible/undesirable side effects

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What is the dose-limiting complication of many antineoplastic drugs?

Bone marrow suppression.

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Fusion proteins

Joining of 2+ proteins in a novel way

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Can fusion proteins occur naturally?

Yes. Ex. CML–> BCR-ABL

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Problems with using native peptides

Lack of receptor specificity
Lack of oral bioavailability (must inject many of these proteins)
Generation of Ab againt proteins
Relative short duration of action

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Solutions to help counteract problems with using native peptides

Add polyethlyene glycol (PEG)–> increases 1/2 life by masking protein from immune system
Use Ab structure as scaffold with no immune recruitment (increase 1/2 life)

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Characteristics of ideal therapeutic Ab

High affinity and specificity
If goal is to recruit immune system, need adequate recruitment of effectors
Long 1/2 life
Few side effects

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Monoclonal Ab administration

Given IV

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Chimeric

30-35% mouse

- more side effects

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Humanized

10% mouse
Fewer side effects
hyper variable region

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Human

Fully human

- Fewest side effects

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Infusion reactions/cytokine release syndrome

Chills, fever, arthralgia, diarrhea, vomiting, hypertension, respiratory distress,

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Nomenclature

[drug company] [target] [source] [mab ending]

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Source identifiers

u=human
o=mouse
xi=chimeric
zu=humanized

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What does knowing the source of an Ab allow you to do?

Predict the severity of possible side effects

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General disease or target

vir=viral
bac=bacterial
lim=immne
les=infectious lesions
cir=cardiovascular

Tumors

col=colon
mel=melanoma
mar=mammary
got=testis
gov=ovary
pr(o)=prostate
tum=misc

Typical fusion protein ending

-cept

2 design strategies for monoclonal Ab

Inhibiting protein function

2. Recruit immune system to all

3 themes for multiple Abs

same target–> multiple disease (e.g VEGF)
different Ab–> same target (different companies)
couple cytotoxic agents to increase effectiveness

Common side effects of cytokines drugs

Anorexia, flu-like symptoms, general malaise, fatigue and can have life-threatening side effects

IL-2 side effects

diarrhea, thrombocytopenia, shock, respiratory distress, coma, fatal hypertension

Erythroid growth factor drugs

Darbepoietin, erythropoietin, methoxy polyethylene glycol epoietin

Myeloid growth factor drugs

Filgrastim (G-CSF), Pegfilgrastim, sargramostim (GM-CSF)

Megakaryocyte growth factors

IL-11, Romiplostim

Mechanism of action of erythroid growth factors

EPO-->RBCs - produced in kidney - work through JAK/STAT activation - inverse relationship between [EPO] and hematocrit normally (ex. chronic renal failure)

Erythroid growth factors pharmacokinetics

EPO-short half-life-->give 3-4x/wk IV | DAPBE--> give weekly MPEG-EPO--> biweekly

Therapeutic uses of erythroid growth factors

Anemia (esp. chronic kidney disease +folate/iron) | High risk surgery

When not to give erythroid growth factors

Athletes | Anemia caused by chemo

Life threatening side effect of erythroid growth factors

Thrombus formation

Other side effects of erythroid growth facotrs

Hypertension (common serious), increased tumor growth, allergic reaction (rare serious)

Myeloid growth factor mechanism of action

Filgrastim--produce neutrophils | Sagramostim--produces any myeloid cells

Myeloid growth factor pharmacokinetics

PEG-FIL--> longer half-life

Therapeutic uses of myeloid growth factors

Cancer chemotherapy

Filgrastim(G-CSF), pegfilgrastim side effects

Allergic reactions, splenic rupture (rare serious). Mild-mod. bone pain (common innocuous)

Sagramostim (GM-CSF)

Capillary leak syndrome, edema (common serious), mod. to severe bone pain, fever, malaise, myalgias (common innocuous). Allergic reactions (rare serious)

Megakaryocyte growth factors mechanism of action

-Increase platelet production

What megakaryocyte growth factor should you never use because antibodies are produced?

Thrombopoietin

Pharmacokinetics of romiplostim

3-4 days

Therapeutic uses for megakaryocyte growth factors

Cancer chemo adjunct | Thrombocytopenia

Side effects of megakaryocyte growth factors

- A fib (common serious) - Fatigue, headache dizziness, mild edema-->fluid dysphena and anemia (hemodilution) (common innocuous) - Hypokalemia (rare serious)

Does IL-11 cause fever?