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Antibodies include immunoglobulin (IG) or antibody molecules including polyclonal antibodies (PABs), and monoclonal antibodies (MABs). Antibody constructs include murine, human (designated "-uMAB"), humanized and chimeric (designated "-ixiMAB" or "-uxiMAB") monoclonal antibodies and antibody fragments.
Antibody-derived binding proteins are bioengineered molecules which are comprised of a portion or fragment of an antibody that is capable of binding a second molecule (molecular target). Usually, the antibody fragment may be the antigen binding, variable region (FAB) of an intact antibody or minimally a portion of an antibody constant region such as the CH1, CH2, or CH3 regions.
Examples of antibody derived binding proteins include Fab, Fab', F(ab').sub.2 and Fv fragments, diabodies, single chain antibody molecules and multispecific antibodies formed from at least two intact antibodies. Other examples include mimetibodies having the generic formula: (V1(n)-Pep(n)-Flex(n)-V2(n)-pHinge(n)-CH2(n)-CH3(n))(m), where "V1" is at least one portion of an N-terminus of an immunoglobulin variable region, "Pep" is at least one bioactive peptide that binds to a second molecule, "Flex" is a polypeptide that provides structural flexibility by allowing the mimetibody to have alternative orientations and binding properties, "V2" is at least one portion of a C-terminus of an immunoglobulin variable region, "phinge" is at least a portion of an immunoglobulin variable hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region and CH3 is at least a portion of an immunoglobulin CH3 constant region, where n and m can be an integer between 1 and 10. A mimetibody mimics properties and functions of different types of immunoglobulin molecules such as immunoglubulin G1 (IgG1), IgG2, IgG3, IgG4, IgA, IgM, IgD and IgE. (source: USPTO #20050095700
Examples of antibody derived binding proteins include Fab, Fab', F(ab').sub.2 and Fv fragments, diabodies, single chain antibody molecules and multispecific antibodies formed from at least two intact antibodies.
Other examples include mimetibodies
A mimetibody is at least one portion of an N-terminus of an immunoglobulin (IG) variable region, containing at least one bioactive peptide that binds to a second molecule, a polypeptide that provides structural flexibility by allowing the mimetibody to have alternative orientations and binding properties, and at least one portion of a C-terminus of an immunoglobulin variable region. A mimetibody contains a "phinge", which is a portion of an immunoglobulin variable hinge region, a CH2 (at least one portion of an immunoglobulin CH2 constant region) and a CH3 (at least a portion of an immunoglobulin CH3 constant region).A mimetibody is a biological "seek-and-destroy missle" which mimics properties and functions of different types of immunoglobulin molecules such as IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgD and IgE.
Therapeutic Uses of Mimetibodies:
Mimetibodies are being studied as antiviral agents (particularly HIV) to reduce or inhibit HIV fusion with a cell membrane and prevent viral entry into target cells.
Infection with human immunodeficiency virus type 1 (HIV-1), the virus that is responsible for acquired immunodeficiency syndrome (AIDS), is one of the leading causes of death worldwide. Most currently available antiretroviral agents inhibit essential HIV-1 enzymes, (reverse transcriptase or protease enzymes).
Current Medical Challenge: Current retroviral therapy is limited by the emergence of drug-resistant HIV viruses, the necessity adhering to complex and voluminous drug regimens, and the potential for toxic side effects of these treatments. Novel classes of safe and effective agents with a low risk of cross-reactivity with other antiretroviral drugs are needed.
Targeting viral entry with mimetibodies may have advantages over the inhibition of the viral life cycle subsequent to HIV infection (Kilby and Eron, N. Engl. J. Med. 348: 2228-2238 (2003)). The HIV-1 envelope glycoprotein is involved in viral entry into the target cell and consists of two noncovalently associated subunits, a surface glycoprotein (gp120) and a transmembrane glycoprotein (gp41). Portions of gp120 bind to the CD4 receptor and chemokine coreceptors (CXCR4 and CCR5) on target cells (Feng et al., Science 272: 872-877 (1996); Dragic et al., Nature 381: 667-673 (1996); Deng et al., Nature 381: 661-666 (1996)). After gp120-CD4-coreceptor binding, the gp41 subunit undergoes a conformational change that promotes fusion of the viral and cellular membrane, resulting in entry of the viral core into the cell, transport to the nucleus and ultimately, proviral integration and expression (Chan et al., Cell 89: 263-273 (1997)).
source
Mimetibodies in the clinical literature
Mimetibody update on FDA.gov
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