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Antibodies in drug delivery
Presented by Saravanan subramaniyam
Department of PharmaceuticsFaculty of Pharmacy
Sri Ramachandra University
INTRODUCTION An antibodies is a protein produced by the immune
system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target.
Antibodies are produced by a specialized group of cells called B-Lymphocytes.
Monoclonal Anti-bodiesMonoclonal antibodies are mono-specific antibodies that are
made by identical immune cells that are all clones of a unique parent cell, in contrast to polyclonal antibodies, which are made from several different immune cells.
Monoclonal antibodies have monovalent affinity, in that they bind to the same epitope. monoclonal antibodies that specifically bind to that sub-stance they can serve to detect or purify that substance.
This is an important tool in biochemistry, molecular biology and medicine.
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General classification Naked mAb Conjugated mAb Bispecific mAb
Naked Monoclonal Antibody: those without any drug or radioactive material
attached to them
Mark the cells for the immune system
Attach to receptors – block binding of growth factors
E.g. 1. Trastuzumab - For advanced breast cancer (HER-2)
2. Rituximab - For B cell non Hodgkin lymphoma (CD 20)
3. Cetuximab - For advanced colorectal cancer ( HER-1)
4. Bevacizumab - For metastatic colorectal cancer (VEGF)
5. Alemtuzumab - For B cell chronic lymphocytic leukemia. (CD 52)
Immune-conjugate:
MAbs conjugated with chemotherapeutic agents e.g. brentuximab vedotin and ado-trastuzumab emtansine.
Brentuximab vedotin, attached to a chemo drug (MMAE) targets the CD30 antigen (present on T and B-cells) in treatment of Hodgkin lymphoma and non-responding anaplastic large cell lymphoma.
Ado-trastuzumab emtansine, attached to DM1 chemo drug, targets the HER2 protein antigen used for curing advanced breast cancer patients.
Bi specific monoclonal antibodies
MECHANISM OF MONOCLONAL ANTIBODY
Monoclonal antibodies for cancer. ADEPT, antibody directed enzyme Prodrug therapy; ADCC: antibody dependent cell-mediated cytotoxicity; CDC: complement-dependent cytotoxicity; MAb: monoclonal antibody; scFv, single-chain Fv fragment.
Production of monoclonal antibody's
Finding solutions for Human use
• In one approach, one takes the DNA that encodes the binding portion of monoclonal mouse antibodies and merges it with human antibody producing DNA, in order to make bacteria produce antibodies that are half mouse and half human.
Production of human monoclonal antibody's
Human monoclonal antibodies are produced by transferring human immunoglobulin genes into the murine genome, after which the transgenic mouse is vaccinated against the desired antigen, leading to the production of monoclonal antibodies.
Routes of administration: Subcutaneously (Rituximab, Trastuzumab, Adalimumab) Intramuscularly (Palivizumab)
Intravenously (IV) route: Preferred because of 100% bioavailability
Route for elimination of antibodies Via uptake & catabolism by reticule endothelial system &
target tissue.
Half-life Chimeric : 4 –15 days Humanized: 3 - 24 days Recombinant human: 11– 24 days Human anti-mouse antibody (HAMA) response develops 7–10
days following exposure to murine antibody
Pharmacokinetics: mAbs
Possible side effects of monoclonal antibodies
• Allergic reactions, such as hives or itching• Flu-like symptoms, including chills, fatigue, fever, and muscle aches and
pains• Skin rashes• Infusion reactions. Severe allergy-like reactions can occur and, in very
few cases, lead to death• Dangerously low blood cell counts. Decreased red blood cells, white
blood cells and platelets• Cardiac complications Certain monoclonal antibodies may cause heart
failure and a small risk of MI• Bleeding. Some of the monoclonal antibody drugs are designed to stop
cancer from forming new blood vessels. There have been reports that these medications can cause bleeding
Applications of Monoclonal Antibodies
Diagnostic Applications- Detects protein of interest either by blotting or immunofloroscence
Therapeutic Applications1. Transplant rejection 2. Cancer3. Autoimmune disorders4. Inflammatory disease
Applications of Monoclonal Antibodies
• Rheumatoid arthritis
• Crohn’s disease, UC
• Psoriasis
• Ankylosing spondilosis
Conjugated monoclonal antibody therapy
• Toxins or radioactive isotopes are bound to the constant region of the MAbs.
• When the MAb binds to the surface cells of a tumour the toxin or radioactivity will kill the cancer cells and all cells within a certain radius (a killing zone).
• In this way cancer cells within the tumour will be killed
Monoclonal antibodies for cancer treatment
Possible treatment for cancer involves monoclonal antibodies that bind only to cancer cells specific antigen and induce immunological response on the target cancer cell (naked antibodies).
mAb can be modificated for delivery of [toxin], radioisotope, cytokine.
What is advances in monoclonal anti-bodies
A Nanobodies/single-domain antibody is a peptide chain of about 110 amino acids long, comprising one variable domain (VH) of a heavy-chain antibody, or of a common IgG 1989 - Raymond Hamers Discovered in camels Completely lack the light chain! Same antigen affinity as their four- chain counterparts Structure makes them more resistant to heat and pH May lead to development of oral nanobodies pills Orally available single-domain antibodies against E. coli-induced diarrhoea in piglets have been developed and successfully tested Other diseases of the gastrointestinal tract, such as inflammatory bowel disease and colon cancer, are also possible targets for orally available sdAbs
Nano-bodies
World antibodies market• Currently more than 200 monoclonal antibodies are in development
• Targeted disorders include cancer, heart disease, infectious diseases and autoimmune diseases
• Market is still in its inception stage,
• Market size estimated at nearly $2.8 billion in 1999,
• Market forecast growth to almost $9.8 billion in 2004.
• Expected therapeutic antibody average annual growth rate is projected at 21.8%
• main market is U.S. market
Antigen specific, can be produced against any type of antigen, hence vast diagnostic applications
Target specificity, a novel therapeutic approach particularly in cancer
Finally, the dreams of Paul Ehrlich who considered antibodies a magic bullets have become reality. Monoclonal antibodies have established themselves as the most important and rapidly expanding class of drugs in oncology. Paul Ehrlich (1854-1915)
Conclusion
Thank you