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Questions and Answers
What are the two principal routes of administration for functional proteins?
What are the two principal routes of administration for functional proteins?
Intravenous and Subcutaneous
Intravenous administration of MAbs provides rapid exposure and onset of effects.
Intravenous administration of MAbs provides rapid exposure and onset of effects.
True
Subcutaneous injections of MAbs can be administered in large volumes.
Subcutaneous injections of MAbs can be administered in large volumes.
False
What kind of charge does the extracellular matrix have?
What kind of charge does the extracellular matrix have?
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The extracellular matrix is highly permeable to all molecules, including negatively charged IgG.
The extracellular matrix is highly permeable to all molecules, including negatively charged IgG.
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What is the primary route of absorption for most proteins larger than 40 kDa, including IgG?
What is the primary route of absorption for most proteins larger than 40 kDa, including IgG?
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Which of the following factors can impact the absorption of MAbs after subcutaneous injection?
Which of the following factors can impact the absorption of MAbs after subcutaneous injection?
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The rate of absorption of a MAb from the subcutaneous space increases with its molecular weight.
The rate of absorption of a MAb from the subcutaneous space increases with its molecular weight.
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How do most MAbs distribute into tissues from blood vessels?
How do most MAbs distribute into tissues from blood vessels?
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The central nervous system is highly permeable to most MAbs.
The central nervous system is highly permeable to most MAbs.
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MAbs can accumulate in diseased tissues.
MAbs can accumulate in diseased tissues.
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What is the name of the receptor involved in recycling of IgG and some MAbs?
What is the name of the receptor involved in recycling of IgG and some MAbs?
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FcRn recycling is less prominent in humans than in rodents.
FcRn recycling is less prominent in humans than in rodents.
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FcRn recycling capacity is unlimited and does not saturate with elevated plasma IgG levels.
FcRn recycling capacity is unlimited and does not saturate with elevated plasma IgG levels.
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FcRn recycling can significantly increase the half-life of MAbs.
FcRn recycling can significantly increase the half-life of MAbs.
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Therapeutic MAb fragments accumulated in the glomerulus are always completely degraded and eliminated without any recycling.
Therapeutic MAb fragments accumulated in the glomerulus are always completely degraded and eliminated without any recycling.
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MAbs in endosomes that are not bound to FcRn undergo proteolytic degradation in the lysosome.
MAbs in endosomes that are not bound to FcRn undergo proteolytic degradation in the lysosome.
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MAb clearance is independent of the specific binding of a MAb to its target.
MAb clearance is independent of the specific binding of a MAb to its target.
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Rituximab, a therapeutic MAb, demonstrates a biphasic pharmacokinetic profile.
Rituximab, a therapeutic MAb, demonstrates a biphasic pharmacokinetic profile.
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What is the name of the MAb that is indicated for the treatment of plaque psoriasis and acts by inhibiting T cell interactions through binding to CD11?
What is the name of the MAb that is indicated for the treatment of plaque psoriasis and acts by inhibiting T cell interactions through binding to CD11?
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The volume of distribution of Efalizumab is constant regardless of the dose administered.
The volume of distribution of Efalizumab is constant regardless of the dose administered.
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What is the approximate renal filtration cut-off size in humans?
What is the approximate renal filtration cut-off size in humans?
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PEGylation of Fab fragments can increase their half-life.
PEGylation of Fab fragments can increase their half-life.
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Diabody format of MAbs lack the Fc region.
Diabody format of MAbs lack the Fc region.
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All therapeutic antibodies are completely safe and do not elicit any immune response in patients.
All therapeutic antibodies are completely safe and do not elicit any immune response in patients.
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MAb aggregates are known to be less immunogenic compared to their monomeric forms.
MAb aggregates are known to be less immunogenic compared to their monomeric forms.
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What is the name of the journal article cited in the presentation that discusses the immunogenicity of MAb aggregates?
What is the name of the journal article cited in the presentation that discusses the immunogenicity of MAb aggregates?
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What are two patient-related parameters that can affect the ADME of MAbs?
What are two patient-related parameters that can affect the ADME of MAbs?
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Target tissue expression and distribution are irrelevant for MAb therapy effectiveness.
Target tissue expression and distribution are irrelevant for MAb therapy effectiveness.
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The ADME of MAbs is always independent of the drug-specific factors.
The ADME of MAbs is always independent of the drug-specific factors.
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Can you list five drug-specific factors that affect the ADME of MAbs?
Can you list five drug-specific factors that affect the ADME of MAbs?
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Study Notes
Biologics 2 - ADME of MAbs
- MAbs (monoclonal antibodies) often don't survive the GI tract due to acidification and proteases.
- Two main administration routes are intravenous (IV) and subcutaneous (SC).
- IV administration provides rapid exposure and direct delivery to the circulatory system.
- SC administration requires injection into the skin and has limitations on volume.
ADME of MAbs - Absorption - Intravenous
- Functional proteins seldom survive the GI tract.
- Two principal administration routes: intravenous (IV).
- IV exposure is rapid and effects are immediate, directly entering the circulatory system
- Controlled administration is standard in clinical settings.
ADME of MAbs - Absorption - Subcutaneous
- Functional proteins seldom survive the GI tract.
- Two principal administration routes: subcutaneous (SC).
- Must be injected into skin; side effects are possible.
- Administered in limited volumes.
- Self-administration is possible.
- Absorption is via lymphatic vessels, and absorbed into the bloodstream
ADME of MAbs - Absorption - Subcutaneous - Site of Absorption
- Absorption occurs in the subcutaneous connective tissue.
- The extracellular matrix is negatively charged and less permeable to negatively charged IgG.
- Glycosaminoglycans (e.g., hyaluronic acid) are part of the ECM.
ADME of MAbs - Absorption - Subcutaneous - Effect of MW on Route of Absorption
- Proteins larger than 40 kDa typically enter the lymphatic system.
- Smaller molecules diffuse directly into blood vessels.
- IgG has a molecular weight of approximately 150 kDa.
ADME of MAbs - Absorption - Subcutaneous - Factors Affecting Absorption
- Various factors impact absorption, including protein/peptide size, formulation, injection volume, molecule charge, and animal factors (species, age).
- Uptake of small molecules (<16 kDa) into capillaries.
- Transport to central lymphatic ducts.
- Percentage of deposition at the injection site.
- Percentage of peripheral lymphatic uptake.
- Potential degradation or binding influence absorption.
ADME of MAbs - Absorption - Plasma Distribution of MAb
- Plasma concentration of MAb assessed after IV or subcutaneous injection in cynomolgus monkeys.
- Subcutaneous absorption is slower than intravenous.
- Maximum concentration after SC administration occurs later (3–4 days).
- Bevacizumab residence time in SC space increases with molecular weight
ADME of MAbs - Distribution - From Blood Vessels to Interstitial Space
- MAbs typically enter the interstitial space through trancytotic vesicles or passive paracellular diffusion through endothelial junctions.
ADME of MAbs - Distribution - Paracellular Diffusion
- Distribution depends on vasculature type (continuous, fenestrated, sinusoidal).
- Central Nervous System (CNS) is impermeable to most MAbs.
- Fenestrated capillaries (e.g., endocrine glands, gastrointestinal tract) are more permeable.
- Sinusoidal capillaries (e.g., liver, bone marrow) have large gaps, facilitating distribution.
ADME of MAbs - Distribution - Accumulation in Diseased Tissue
- Accumulation of anti-TNF IgG in inflamed tissues.
- PEG-modified antibodies are often found in greater concentrations in inflamed tissue, compared to unmodified IgG
ADME of MAbs - Recycling - Neonatal Fc Receptor (FcRn)
- FcRn-mediated transcytosis plays a role in recycling IgG.
- Post-natal transfer in rodents; in utero transfer in humans.
- IgG is released by FcRn in the fetal/neonatal circulation at physiological pH.
ADME of MAbs - Recycling - FcRn (continued)
- FcRn recycles about 2/3 of IgG molecules.
- FcRn capacity is limited by elevated plasma IgG levels.
ADME of MAbs – FcRn Recycling
- Wild-type mice recycle MAb better than mutants lacking FcRn receptors.
ADME of MAbs - IgG Trapped in Kidneys
- MAb fragments accumulated in the glomerulus are excreted or recycled via FcRn-mediated transcytosis.
ADME of MAbs - Elimination by Pinocytosis
- MAbs that don't bind to FcRn are degraded in lysosomes within cells by pinocytosis.
ADME of MAbs - Elimination by Receptor-Mediated Endocytosis
- Leucocytes and endothelial cells eliminate MAbs through receptor-mediated endocytosis.
ADME of MAbs - Clearance via Specific Binding
- Clearance is saturable in some cases (e.g., rituximab).
- Clearance mechanisms include target-mediated catabolism and non-linear clearance, as well as simple linear clearance after saturation.
- Clearance sometimes occurs via phagocytosis.
ADME of MAbs - Target-Mediated Drug Deposition
- Efalizumab example.
- Lower doses of antibody rapidly disappear from the plasma after binding to CD11, showing receptor localization and internalization.
- Greater doses can saturate receptor, showing non-specific catabolism
ADME of MAbs – Renal Excretion
- MAb fragments undergo renal excretion.
- Size filters play a role (e.g., renal filtration cut-off for humans).
ADME of MAbs - PEGylation
- PEGylation increases the half-life of Fab fragments
- Full-size IgG has long half-life, while Fab fragments have a short half-life on their own
- PEGylation increases the half-life of Fab fragments
ADME of MAbs - Conformational Effects on PK
- Antibody conformation affects pharmacokinetic (PK) profile and tissue/target levels.
- MAb fragments may have different clearance profiles (e.g., IgG versus a diabody) based on whether/how its Fc region is present.
Therapeutic Antibodies - Immunogenicity
- The immune system can generate anti-drug antibodies (ADAs).
- MAb aggregation is highly immunogenic.
- Antibody aggregation can trigger immune responses.
Summary - ADME of MAbs - Factors
- Key drug-specific factors include molecular weight, structure, charge, glycosylation, PEGylation, FcRn and FcyR binding.
- Key patient-related factors include route/site of administration, blood flow, interstitial volume pressure, disease status, target tissue expression, and target distribution.
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Description
This quiz covers the ADME (Absorption, Distribution, Metabolism, and Excretion) process of monoclonal antibodies (MAbs), focusing on different administration routes. Learn about the differences between intravenous and subcutaneous administration, including their advantages and limitations. Explore how functional proteins react within the gastrointestinal tract and their implications in clinical settings.
