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Pharm Block 1 > 9 - Pharmacology of Therapeutic Antibodies > Flashcards

9 - Pharmacology of Therapeutic Antibodies Flashcards

1
Q

What are the two major functions of antibodies?

A
  1. Recognize and bind antigen via antigen-soluble proteins

2. Induce immune responses after binding antigen

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2
Q

What do the variable and constant regions of the antibody do?

A

Variable: mediates binding

Constant: mediates immune response after binding

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3
Q

All therapeutic antibodies are what type?

A

IgG

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4
Q

What are monoclonal antibodies?

A

Monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell.

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5
Q

What are properties of monoclonal antibodies?

A

Highly specific
High affinity for the antigen
Long t1/2 in vivo

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6
Q

What are the four types of therapeutic monoclonal antibodies?

A

Human (umab)

Murine (momab) - whole antibody of mouse origin

Chimeric (ximab) - part human and part mouse origin

Humanized (zumab) - part human and part mouse origin

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7
Q

What is consistent between human, murine, chimeric, and humanized antibodies?

A

The Fc (stalk) portion in all of them is human.

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8
Q

What do o(s), vi(r), ba(c), and li(m) mean when they’re in names of nomenclature of monoclonal antibodies?

A

o(s): bone
vi(r): viral
ba(c):bacterial
li(m): immune

These are the targets of the monoclonal antibodies.

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9
Q

What do le(s), ci(r), mu(l), and ki(n) mean when they’re in names of nomenclature of monoclonal antibodies? ?

A

le(s): infectious lesions
ci(r):cardiovascular
mu(l):musculoskeletal
ki(n): interleukin

These are the targets of the monoclonal antibodies.

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10
Q

What do the co(l), me(l), ma(r), go(t), and go(v) mean when they’re in names of nomenclature of monoclonal antibodies?

A 
co(l): colonic tumor 
me(l): melanoma 
ma(r): mammary tumor 
go(t): testicular tumor 
go(v): ovarian tumor

These are the targets of the monoclonal antibodies.

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11
Q

What do pr(o), tu(m), neu(r), and tox(a) mean when they’re in names of nomenclature of monoclonal antibodies?

A

pr(o): prostate tumor
tu(m): miscellaneous tumor
neu(r):nervous system
tox(a): toxin as target

These are the targets of the monoclonal antibodies.

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12
Q

What are the four word parts used in the nomenclature of monoclonal antibodies that describe the source of the antibodies? Where is this located in the name?

A

u - human

o - mouse

xi - chimeric

zu - humanized

This part of the name is located after the name of the target.

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13
Q

What is the target and source of abciximab?

A

Chimeric (xi) monoclonal antibody used on the cardiovascular (xi) system

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14
Q

What is the target and source of adalimumab?

A

human (u) monoclonal antibody used against an immune (lim) target.

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15
Q

What is the target and source of Tositumomab?

A

Murine (o) monoclonal antibody used against a tumor (tum).

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16
Q

What is the target and course of Palivizumab?

A

Humanized (zu) monoclonal antibody used against a virus (vi).

17
Q

What is the bioavailability of monoclonal antibodies in subQ, intramusclar, and IV adminitration? What is their distribution?

A

Subcutaneous: 24-95% bioavailability
Intramuscular: 24-95% bioavail.
Intravenous: 100% bioavail.

These are extracellularly distributed. They do NOT cross the BBB.

18
Q

What is the function of the Neonatal Fc receptor (FcRn) for IgG? At what pH does it bind?

A

Protects IgG from degradation and prolongs serum half life for long-lasting effects.

Transfers passive immunity to fetus.

Binds Fc region of IgG at pH <6.5 but not 7.5.

19
Q

What does the FcRn bind most strongly? What doesn’t bind at all?

A

IgG1, 2, and 4 all bind equally well. IgG3 is the one that binds more weakly.

Murine IgG does not bind human FcRn. Fab or Fab2 antigen fragments lack an Fc region and also do not bind FcRn.

20
Q

How is IgG recycled via the FcRn recepter? What is the result of this?

A

There’s circulating IgG from an IV infusion and these are taken up by endocytosis.

The interior of the endosome becomes acidic and the IgG will binds FcRn to protect it from degradation. Those that don’t bind are degraded.

Those that bind can be recycled through the PM on the luminal or abluminal side of the membrane.

Once they fuse with the membrane, the higher pH causes them to be released from the receptor.

This results in a prolonged half life of IgG.

21
Q

What IgG antibodies have the longest half-lives?

A

IgG1, IgG1, and IgG4 have a half life of ~21 days because they bind FcRn

IgG3 ~7 days

22
Q

What are the half lives of monoclonal antibodies in humans vs. mice? What about the half life of antibody fragments-Fab?

A

Human: ~21 days because they bind FcRn

Mice: 12-48 hours because they don’t bind FcRb

Antibody fragments-fab ~11-27 hours because they don’t bind FcRn.

23
Q

What are the three mechanisms of actions of monoclonal antibodies?

A
  1. Direct effects such as antagonism or neutralization (inactivating or competitively inhibiting a soluble antigen) More commonly occurs with mouse Fab fragments
  2. Complement-dependent cytotoxicity (CDC): Fc receptor binds complement and activates it to cause lysis
  3. Fc Receptor mediated effector functions such as antibody-dependent cellular cytotoxicity (ADCC)
24
Q

What are the adverse side effects associated with using monoclonal antibodies?

A

Generally safe and well-tolerated.

Side effects that occur are related to mechanism of action specific for a particular antibody (such as a risk of bleeding with anti-platelet Ab) or based on the general class of the Ab you’re giving.

25
Q

What side effects would be associated with specific classes of monoclonal antibodies? What occurs?

A

Immunogenicity to a general drug class. This would cause generation of endogenous antibodies against the therapeutic antibody.

This can neutralize the effect of the therapeutic antibody or cause a hypersensitivity reaction that’s local or systemic (anaphylaxis).

26
Q

What increases the immunogenicity of an antibody?

A

The more of the antibody that isn’t human, the more immunogenic it is. For example, the murine antibody has high immunogenicity because it’s origin is 100% mouse.

Small doses are also more immunogenic than large doses.

27
Q

What are biosimilar monoclonal antibodies? What is an advantage to them?

A

Organic chemicals that are chemically distinct but therapeutically similar and similar in regards such as pharmacokinetics and immunogenicity.

Lower cost via competition.

Pharm Block 1 (11 decks)

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