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:

  1. Immune mediated disease
  2. Graft rejection
  3. Inflammatory bowel disease – CD, UC
  4.  RA, PSA, AS, SLE, CAPS
  5. Asthma
  6. Psoriasis
  7. Hematological malignancies and solid tumors
  8. NHL, CLL, Colorectal Ca, HNC, Breast Ca
  1.  Angiogenesis inhibitors
  2. Antiplatelet
  3. Diagnostic uses
  4. CEA-Scan
  5. Myoscint
  6. Verluma
  7. ProstaScint
  1. Grouping blood types and identifying viruses
  2.  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

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.