Monoclonal antibodies

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MONOCLONAL ANTIBODIES AS DRUG CARRIERS {Targeted drug delivery system} :

MONOCLONAL ANTIBODIES AS DRUG CARRIERS {Targeted drug delivery system} SUBMITTED BY D.BASKER REDDY M.pharm , Pharmaceutics R.R College of pharmacy

TOPICS:

TOPICS Introduction production of monoclonal antibodies Types of monoclonal antibodies Applications Problems in delivery of monoclonal antibodies Recent approaches

Structure of antibody:

Structure of antibody

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Labeled as “MAGIC BULLETS” Structure and mechanism action are similar to normal antibody Carriers for drug targeting Mabs are mostly IgG or IgE type FDI approved 9 Mabs for cancer treatment 5 are for hematological malignances 4 are for solid tumors Reduces toxicity of anti cancer drugs

MONOCLONAL & POLYCLONAL:

MONOCLONAL & POLYCLONAL Monoclonal antibody : An antibody is called “MONOCLONAL” when each immunoglobulin is produced by a single clone of hybridoma cells, which is formed by the fusion of a β -cell with a tumor cell or myeloma cell Monoclonal antibody {Mabs} is a single pure homogenous type of antibody Polyclonal antibody: It represents the antibodies from multiple clones of β -lymphocytes, and therefore bind to a number of epitope

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polyclonal monoclonal Derived from different B-cell lines Batch to batch variation affecting Ab reactivity and titre NOT powerful tools for clinical diagnostic tests Derived from single B-cell clone line Mabs produce Reproducible, predictable and potentially inexhaustible supply of Ab with exquisite specificity Enable the development of secure immunoassay systems

Mabs production by Hybridoma technology Discovered by George Kohler and Cesar Milstein in 1975 :

Mabs production by Hybridoma technology Discovered by George Kohler and Cesar Milstein in 1975

Types of monoclonal antibodies:

Types of monoclonal antibodies

Murine monoclonal antibody:

Murine monoclonal antibody Whole of the antibody is of murine origin Produced by Hybridoma technology Major problems with murine mabs include Reduced stimulation of cytotoxicity Formation of complexes after repeated administration Allergic reactions Anaphylactic shock Ex. Aflimomab, Abagovomab

Chimeric monoclonal antibody:

Chimeric monoclonal antibody Chimeric antibodies Composed of murine Variable regions fused onto human constant regions developed by Recombinant DNA technology Antibodies are Approximately 65% Human origin This reduces immunogenicity thus increases serum-half life Ex. Basiliximab, Cetuximab

Humanised monoclonal antibody:

Humanised monoclonal antibody Humanised antibodies are Produced by grafting murine hypervariable domains into human antibodies Antibodies are approximately 90-95% human origin These bind weakly to the antigens Ex. Apolizumab, Atlizumab

Human monoclonal antibody:

Human monoclonal antibody 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 Ex. Belimumab, cixutumumab

Applications of monoclonal antibodies:

Applications of monoclonal antibodies Therapeutic applications Transplant rejection cardiovascular disease cancer Infectious diseases Inflammatory diseases Diagnostic applications Biosensors Clinical applications purification of drugs , imaging the target

Mabs for cancer treatment:

Mabs for cancer treatment Monoclonal antibodies act by several mechanisms

ADCC:

ADCC Immunoglobulin's clustered on the surface of the targeted cells and exposes its tail {F c} region, to be recognized by the Fc receptors present on the surface of the macrophages and neutrophils. This causes Lysis of tumor cell.

RADIOIMMUNOTHERAPY :

RADIOIMMUNOTHERAPY Involves the use of radioactively conjugated murine antibodies against cellular antigens Emitted radiation causes tumor cell lysis More applicable to lymphomas as they are highly radiosensitive malignancies

ADEPT (Antibody mediated Enzyme prodrug therapy):

ADEPT (Antibody mediated Enzyme prodrug therapy) An antibody developed against a tumor antigen is linked to a drug -activating enzyme and injected to the blood subsequent systemic administration of non-toxic agent or prodrug results in its conversion to a toxic drug & results in cytotoxic effect

IMMUNOLIPOSOMES:

IMMUNOLIPOSOMES These are antibody conjugated liposome's Liposome's can carry drugs or therapeutic nucleotides and when conjugated with monoclonal antibodies, deliver the entrapped drug or toxin specially to the target cells

IMMUNOTOXINS:

IMMUNOTOXINS Immunotoxins are proteins that contain a toxin along with an antibody that binds specifically to target cells. All protein toxins are work by enzymatically inhibiting protein synthesis. Various plant & biological toxins have been genetically fused/chemically conjugated with the antibodies that bind to cancer cells.

Antibody drug conjugates:

Antibody drug conjugates Antibody drug conjugates are monoclonal antibodies (mAbs) attached to biologically active drugs by chemical linkers with liable bonds Reduces side effects and show wide therapeutic window Doxorubicin, Duanomycin, Chlorambucil etc. can be conjugated with monoclonal antibodies

Fragments of Mabs:

Fragments of Mabs Fab and F( ab ) 2 are less immunogenic but have greater tumor penetration power than normal antibody and are helpful in detecting smaller lesions (<2cm) not seen on computed tomography ScFv are mainly used as delivery vehicles for cancer therapy

Slide 22:

Mabs act as Interleukin-2(IL-2) receptor antagonist Inhibits IL-2 mediated stimulation of lymphocytes, a critical step in the process of allograft rejection Mainly prevents acute rejection of kidney transplants Mabs for Autoimmune disea Mabs neutralize the cytotoxic activity of Tumor necrosis factor(TNF) and inhibits the growth stimulatory activity of TNF. control rheumatoid arthritis, crohn’s disease and ulcerative colitis Mabs for transplant rejection Mabs for Autoimmune disease

DRUG LOADING:

DRUG LOADING Generally, a higher number of drug molecules are attached to a single targeting antibody. But as the number of drug molecules attached per antibody molecule increases, the target binding activity of the antibody decreases. To overcome this problem, carriers like dextran, hydroxymethylpropylamineacrylamine (HPMA), and serum albumin can be used to attach more number of drug molecules per targeting antibody. Antibody with 2-3 drug molecules shown satisfactory tumour binding site

Problems of delivery of monoclonal antibodies:

Problems of delivery of monoclonal antibodies

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slow elimination of monoclonal antibodies from the blood poor vascular permeability low and heterogeneous tumor uptake Cross reactivity with normal tissues Metabolism of monoclonal antibody conjugates

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May bind with the targeted epitopes present on other tissues, which may lead to the damage of normal cells Antibody-drug conjugates may induce their own immunogenicity and be removed from the system before interacting with the target Diseased cells may alter their expression of ligand thereby rendering targeting more difficult

Slide 27:

Tumor uptake may be increased through administering high doses Use of certain agents to increase tumor vascular permeability Tumor retention of antibody conjugates may be improved by inhibition of metabolism, by using more stable linkages Alternatively, normal tissue retention may be decreases through the use of metabolisable chemical linkages inserted between the antibody and conjugated moiety

NEW APPROACHES :

NEW APPROACHES BISPECIFIC ANTIBODIES ANTIBODY+SUPER ANTIGEN

Bispecific antibodies:

Bispecific antibodies It consists of two antibodies with specificity for distinct antigens and immune effectors Cell Of the 2 paratopes, one can Be directed against a tumor Antigen and other against a T-lymphocyte. The Fc region additionally binds to a Fc receptor present on a macrophage/a natural killer cell. This mechanism cause tumor cell lysis

Antibody + super antigen:

Antibody + super antigen In this approach antibody is linked with super antigen ex. Staphylococcal enterotoxin A These toxins are binding directly to macrophages and activating them for example, if the super antigen is linked to an antibody structure with specificity for a tumor associated antigens, it targets the activated macrophages to the tumor cell

Disadvantages of Mabs:

Disadvantages of Mabs Mabs production, a time consuming process because entire process requires 3-4 months for one fusion experiment Average affinity of Mabs are generally lower than polyclonal antibodies single Mab is a single chemical and any physical/chemical treatment that affects one molecule will affect all Mabs in that production

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