Monoclonal Antibodies
Immune system
- Protective nature, perception of self vs foreign
- Refers to the resistance exhibited by the host towards injury caused by microorganisms and their products.
- Innate & Acquired
- Active & Passive
In 1986 – 1st monoclonal antibody(OKT-3/muromonab CD3) produced & approved for use of organ transplant rejection
Hybridoma Technology & Production
- Identify surface receptors associated with major cancers
- Search genome databases for genes regulating receptors
- Compare gene sequences to that of living cancer cells
- Use microarrays to find genes active in cancer but not in normal cells
- Identify target receptor proteins
- Other methods
- Transgenic mice – the embryonic stem cell method – making “knocked out” antibodies
- Phase display
Types of Monoclonal Ab
- First generation mAB
- Murine Antibodies – derived from rat, rabbit etc.
- Second generation mAB
- Chimeric AB – Infliximab, Rituximab, Abciximab
- Humanized AB – Daclizumab, Vitaxin, Herceptin
- Primatized AB
Other Classification of MAbs
- Naked Mabs – with out any drug or radioactive material attached to them
– e. g. Transtuzumab, Rituximab, Cituximab
- Conjugated/Tagged/Labeled/Loaded Mabs
– with radioactive particle
– e.g. Ibritummomab tiuxetan – for B-cell NHL
Mechanism of Action of MAbs
Blocking of the function of target antigen i.e. T-lymphocytes, B-lymphocytes, TNF alpha and Interleukin
Cytotoxicity to the cell expressing target antigen by ADCC or CDC
Inhibition of growth factors like EGF e.g. Cetuximab act as EGFR inhibitor
Pharmacokinetic
A. Antibody Absorption
Intravenous (IV) administration
Some extravascular administration
Subcutaneous (SC) administration – Adalimumab, Efalizumab, Omalizumab
Intramuscular (IM) administration – Palivizumab
Intravitreal administration – Ranibizumab, (Bevacizumab –off label drug)
B. ANTIBODY DISTRIBUTION:
MABs, diffuse across vascular endothelial cells very slowly, as they are polar.
Higher concentrations are observed in tissues with leaky vasculature (e.g., bone marrow and spleen)
IgG antibodies show very little distribution to the brain.
C. ANTIBODY ELIMINATION
Dose-dependent elimination (e.g., trastuzumab, rituximab, gemtuzumab, and panitumumab)
Elimination of large immune complexes may follow the nonlinear elimination kinetics (omalizumab, which is thought to interact with soluble target IgE)
Target-meditated elimination is capacity limited (saturable) because of finite expression of the target.
Dose, the expression level of the target, a function of the kinetics of receptor internalization and intracellular catabolism.
MOA for adverse effects :
Xenogenetic nature of MAbs
Suppressions of physiological function
Activation of inflammatory cell and mediators
Allergic reactions (due to massive cytokines release) – Skin rashes
- Flu like symptoms – chills, fatigue, fever, muscle ache & pain
- Nausea & Diarrhea
- Infusion reaction
- Bone marrow depression – leucopenia, thrombocytopenia & anemia
- Increased risk of infection and cancer development
- Reactivation of Tuberculosis
- hypogammaglobulinemia
Uses:
- Immune mediated disease
- Graft rejection
- Inflammatory bowel disease – CD, UC
- RA, PSA, AS, SLE, CAPS
- Asthma
- Psoriasis
- Hematological malignancies and solid tumors
- NHL, CLL, Colorectal Ca, HNC, Breast Ca
- Angiogenesis inhibitors
- Antiplatelet
- Diagnostic uses
- CEA-Scan
- Myoscint
- Verluma
- ProstaScint
- Grouping blood types and identifying viruses
- Purification of proteins and drugs
- Diagnostic uses
- CEA-Scan – Arcitumomab linked to Tc 99m for colon & rectal cancer
- Myoscint – Imcriromab linked to Indium(111 In), for MI
- Verluma – Nofetumomab linked to Tc 99m, for SCLC
- ProstaScint – Capromab Pendetide linked Indium (111m In) for prostate cancer
- Other uses
- Grouping blood types and identifying viruses
- Purification of proteins and drugs