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What is antibodies
An antibody is a protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target. Monoclonal antibodies (mAb) are antibodies that are identical because they were produced by one type of immune cell, all clones of a single parent cell.
Polyclonal antibodies are antibodies that are derived from different cell lines.
Isotypes According to differences in their heavy chain constant domains, immunoglobulins are grouped into five classes, or isotypes: IgG, IgA, IgM, IgD, and IgE. IgG: IgG1 (66%), IgG2 (23%), IgG3 (7%) and IgG4 (4%) , blood and tissue liquid. IgA:IgA1 (90%) and IgA2 (10%), stomach and intestines IgM: normally pentamer, ocassionally hexamer, multiple immunoglobins linked with disulfide bonds IgD:1% of proteins in the plasma membranes of B-lymphocytes, function unknown IgE: on the surface of plasma membrane of mast cells, play a role in immediate hypersensitive and denfensive for parasite
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1890 Von Behring and kitasato discovered the serum of vaccinated persons contained certain substances, termed antibodies 1900 Ehrlich proposed the side-chain theory 1955 Jerne postulated natural selection theory. Frank Macfarlane Burnet expended. Almost the same time, Porter isolated fragment of antigen binding (Fab) and fragment crystalline (Fc) from rabbit y-globulin. 1964 Littlefield developed a way to isolate hybrid cells from 2 parent cell lines using the hypoxanthine-aminopterin-thymidine (HAT) selection media.
1975 Kohler and Milstein provided the most outstanding proof of the clonal selection theory by fusion of normal and malignant cells 1990 Milstein produced the first monoclonal antibodies.
Chemotherapy
Shortcomings:
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Nature of cytotoxin Lack of in vivo selectivity The mechanism of anti-proliferation on cells cycle, rather than specific toxicity directed towards particular cancer cell Host toxixity: treatment discontinued, most of them had bad side-effects, such as no appetites, omit, lose hair
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mAbs was modified for delivery of a toxin, radioisotope, cytokine or other active conjugates.
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it is also possible to design bispecific antibodies that can bind with their
Fab regions both to target antigen and to a conjugate or effector cell
ADEPT, antibody directed enzyme prodrug therapy; ADCC, antibody dependent cell-mediated cytotoxicity; CDC, complement dependent cytotoxicity; MAb, monoclonal antibody; scFv, single-chain Fv fragment.
Carter P: Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 2001;1:118-129
Strategy of a direct or in direct induction of apoptosis in targeted cancer cells 1. mAbs target growth factor receptors to exert a direct effect on the growth and survival of the cancer cells by antagonizing ligand-receptor signaling.
2. mAbs can target to cell surface antigens and directly elicit apoptotic signaling.
Until Feb 28, 2005, 18 mAbs were approved by FDA, which were applied in the treatment of organ transplant, Cancer, Asthma, Hematopoietic malignancies and psoriasis.
The first approved mAbs was OKT-3, which is a murine IgGa2 protein to deplete T cells in patients with acute rejection of renal allotransplant.
HAMA response
Jancie, M Recheit, etal. Nature biotechnology, 2005, Sep,Vol. 23, No.9 Stamatis-Nick C. J Allergy Clin. Immunol, Oct. 2005
mAbs development
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Transgenic plants: transgenic tobacco plants to produce IgA. Transgenic animals: transgenic mouse to make humanized IgG. (Abgenix,CA)
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Questions?