Antibody Pharmacokinetics Flashcards
Top 6 of the 10 protein drugs
- Humira
- Rituxan
- Herceptin
- Avastin
- Remicade
- Enbrel
How many mono-clonal antibodies are currently approved for clinical use?
- 75
- several hundred in current clinical developement
What is an important consideration between the different isotypes of antibodies?
- molecular weight
- serum half-life
Characteristics of IgM
- pentamer/hexamer
- 950 kD, 1150 kD (largest one!)
- serum half-life of 5
- primary Ab responses: secretory immunoglobulin
Characteristics of IgD
- monomer
- 175 kD
- Serum half-life of 3
- Unknown biological properties
- Useful as a B cell marker
Characteristics of IgG
- Monomer
- 150 kD
- Serum half-life of 23 (longest one!)
- Hallmark of secondary immune responses
Characteristics of IgA
- Monomer
- 160 kD, 400 kD
- Serum half-life of 6
- Main secretory immunoglobulin
Characteristics of IgE
- Monomer
- 190 kD
- Serum half-life of 2.5
- Allergic and anti-parasite responses
What drives the pharmacokinetics of antibody therapy?
-Compliment
What is the most prevalent antibody isotype in man?
- IgG antibodies
- All that are approved at IgG
- Very large protein (150,000 Da)
What is the FAB site?
Fragment of antigen binding
What is the FC site
Fraction that crystalizes
-precipitates from solution
What is a polyclonal IgG antibody?
- Rats are immunized and it leads to propagation of genetically distinct Ab-producing cells
- Many clones, each with a different protein that they are making
- Using animals is not always desirable and it is difficult
What is a monoclonal antibody?
- Ab cells may be fused with myeloma (tumor cells) and cloned, allowing for production of large quantities of Ab from a monoclonal population of Ab producing cells
- when done in vitro, all will have the same genetics and same proteins without having to use an animal
How do antibodies complete neutralization of a toxin or xenobiotic (Synthetic toxin)
-the antibody therapy can prevent the activity of the soluble substance Examples: -anti-digoxin Fab therapy -adalimumab -bevacizumab -infliximab -alircumab MOA: 1: Bind, 2: neutralize, 3: Affect PK
How do antibodies eliminate cells?
-antibody mediated clearance
-Example:
Anti-CD4 IgG can attach to the CD4 on a T-cell to clear the cell.
-opsonizes the cell, marks it for destruction, depletes the cells for the target
(Used in cancer treatment)
Example therapies:
-basiliximab
-daclizumab
-muromonab-CD3
-rituximab
How do antibodies cause alteration of cell function?
Example: Alteration of cell function/ cell signaling
-abciximab (anti-CD41) prevents platelet aggregation
-useful in treatment of acute MI and prophylaxis
-CD41 (GPIIb/IIIa fibrinogen receptor)
-Abciximab has a chimeric Fab against CD41 which binds to surface receptor and prevents signaling of receptor with out causing damage to the cell
-Additional examples:
basiliximab, daclizumab, efalizumab
How to antibodies cause drug delivery?
Increasing the efficiency of drug delivery to desired sites
Example: Gemtuzumab ozogamicin
-The intracellular release of ozogamicin and induction of cell death
-Ozogamicin is the toxin (chemotherapeutic drug) that delivers the toxin to the tumor cell
-This decreases toxicity to healthy tissues A
Additional Examples:
-ibritumomab tiuxetan, ado-trastuzumab emtansine, brentuximab vedotin
What are the general expectations of antibody pharmacokinetics
- Good absorption following SQ or IM dosing
- 50-100% oral bioavailability
- Bi-exponential dispostion
- long terminal half-life (20 days) and low rates of clearance (10ml/h)
- small volume of distribution (3-9L)
- some have long half-lives maybe 6 months
What are the elimination mechanisms for peptides and proteins?
- ) Fluid phase endocytosis (& catabolism)
- ) Renal filtration (& catabolism and excretion)
- ) Phagocytosis
- ) “Component-specific” - receptor mediated endocytosis
- ) “Component-specific” - receptor mediated protection
- ) “Drug- specific” receptor mediated endocytosis
Describe the elimination mechanism of Fluid-Phase Endocytosis and Proteolysis
-Considered to be “non-specific”
-Proteins and peptides broken down to component amino acids
-degradation products are not likely to be toxic
Mechanism:
1.) There is protein and fluid outside of the cell (interstitial fluid/plasma)
2.) Then endocytosis occurs when there is “cell drinking” and captures some extracellular fluid and some of the protein
3.) Before endocytosis occurs, the cell exchanges Na+ for H+ but after endocytosis occurs, H+ influxes into the cell
-it drops PH of the fluid to about 5 or 6 (starts to denature the protein)
-once it goes to the lysosome even more harsh conditions occur (enzymes that chop up the protein)
-Once in the lysosome it becomes catabolized into amino acids
the half-life for this type of AB process is 20-30 days
Describe the elimination mechanism of renal filtration/ phagocytosis and proteolysis
- Size specific mechanism of elimination
- phagocytosis may be a primary mechanism of elimination for proteins and aggregates greater than 400 kDa
- Renal filtration & subsequent proteolysis is often a primary mechanism of elimination when MW is less that 50 kDa
How much of IgG is eliminated unchanged in urine?
Essentially nothing comes out of the urine unchanged due to re-uptake in the kidney
Describe the renal clearance of Mab and antibody fragments
- Renal CL of protein is underestimated by glomerular sieving coefficient
- current data suggests that renal CL accounts
