Targeting antibodies

Antibody targeting Use of mono-and bispecific antibodies to target components of angiogenic blood vessels (e.g., VEGF receptors, endoglin, L19 antigen) to deliver specific angio- and/or tumoricidal activity... 

The epidermal growth factor receptor 2 (HER-2) is a protein found on the surface of cells. Heterodimerization of HER-2 activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. HER-2 is found at abnormally high levels on the surface of many types of cancer cells, which may divide excessively. Antibodies targeting HER-2 (e.g., trastuzumab) are used as antineoplastic agents. 

In addition to antibodies targeting the CD3 subunit of the TCR complex, antibodies against the a and (3 subunits of the TCR have been tested as therapeutic agents. A benefit for the treatment experimental autoimmune encephalomyelitis or collagen induced arthritis could be shown in animal models [8]. 

Straubinger, R. M., Lopez, N. G., Debs, R. J., Hong, K., and Papahadjopoulos, D. (1988). Liposome-based therapy of human ovarian cancer Parameters determining potency of negatively charged and antibody-targeted liposomes, Cancer Res.. 48, 5237-5245. 

Baldwin R.W. (1985) Monoclonal antibody targeting of anti-cancer agents. EurJ Cancer Clin Oncol, 21, 1281-1285. 

The discovery of monoclonal antibodies and combining them with polymeric prodrugs is the newest approach to overcome the lack of selectivity for disposition in target tissue (23). Recently the selectivity of antibody-targeted polymeric anthracycline antibiotics to T lymphocytes was accomplished (25). In addition decreased immunogenicity of proteinaceous conjugates with IgG and human transferrin has been reported (26). 

Fig. 13 Diagrammatic representation of two types of antibody-targeted systems. Drug is either covalently linked directly to the antibody or is contained in liposomes that are targeted by attached antibodies.

Figure 21.1 The basic design of an immunotoxin conjugate consists of an antibody-targeting component crosslinked to a toxin molecule. The complexation typically includes a disulfide bond between the antibody portion and the cytotoxic component of the conjugate to allow release of the toxin intracellularly. In this illustration, an intact A-B toxin protein provides the requisite disulfide, but the linkage also may be designed into the crosslinker itself.

Covalent attachment of antibody molecules to liposomes can provide a targeting capacity to the vesicle that can modulate its binding to specific antigenic determinants on cells or to molecules in solution. Antibody-bearing liposomes may possess encapsulated components that can be used for detection or therapy (Figure 22.17). For instance, fluorescent molecules encapsulated within antibody-targeted vesicles can be used as imaging tools or in flow cytometry... 

Carter, R, Smith, L., and Ryan, M. (2004) Identification and validation of cell surface antigens for antibody targeting in oncology. Endocr. Relat. Cancer 11, 659-687. 

Heath, T.D., Montgomery, J.A., Piper, J.R., and Papahadjopoulos, D. (1983) Antibody-targeted liposomes Increase in specific toxicity of methotrexate-g-aspartate. Proc. Natl Acad. Sci. USA 80, 1377-1381. 

Matthay, K.K., Heath, T.D., and Papahadjopoulos, D. (1984) Specific enhancement of drug delivery to AKR lymphoma by antibody-targeted small unilamellar vesicles. Cancer Res. 44, 1880-1886. 

Schrama, D., Reisfeld, R.A., and Becker, J.C. 2006. Antibody targeted drugs as cancer therapeutics. Nature Reviews Drug Discovery 5(2), 147-159. 

The role of bevacizumab, a monoclonal antibody targeted against vascular endothelial growth factor, in MBC is currently not clearly defined. 

However, luminescence-based detection techniques often require a high number of steps. Consider ELISA as an example. As a first step, the sample is introduced into a 96-well plate an antibody targeting the antigen of interest has been immobilized to the wells of the plate. After a rinse, the wells contain the antibody and any bound antigen. However, although the antigen has been isolated, the protocol is nowhere near completion. The remaining steps include another antibody (different from the first) to form a sandwich assay, a secondary antibody with an enzymatic label, and a substrate that is luminescent when activated by the enzyme. Finally, the sample is analyzed by relatively expensive detection optics to determine the amount of analyte that was captured in the assay. The steps are illustrated in Fig. 14.1a. 

B. Packard and M. Edidin, Site-directed labeling of a monoclonal antibody Targeting to a disulfide bond, Biochemistry 25, 3548-3552 (1986). 

Tumor Necrosis Factor There are two types of tumor necrosis factor TNF-a and TNF- 8. Of the two, TNF-a has been studied in more detail. TNF-a is a 157 amino acid polypeptide. It is a mediator of immune regulation, including the activation of macrophages and induction of the proliferation of T cells. Another TNF-a function is its cytotoxic effects on a number of tumor cells. Recent research, however, concentrates on its property in the stimulation of inflammation, particularly in the case of rheumatoid arthritis. Clinical trials are being conducted with drugs to block TNF-a with anti-TNF-a monoclonal antibodies. These antibodies target the excessive levels of TNF-a in the synovial fluid of joints and provide relief to sufferers of rheumatoid arthritis (Exhibit 4.10). 

Overview of Laser Microbeam Appiications as Reiated to Antibody Targeting... 

Figure 1.1. Schematic representation of four major liposome types. Conventional liposomes are either neutral or negatively charged. Stealth liposomes are sterically stabilized and carry a polymer coating to obtain a prolonged circulation time in the body. Immunoliposomes are antibody targeted liposomes and can consist of either conventional or sterically stabilized liposomes. Positive charge on cationic liposomes can be created in various ways. Reproduced from reference [112] with permission.

A variant of the original immunotoxin approach is the so-called immunocytokines. In these constructs the antibody targeting moiety is maintained, but the toxin as the effector molecule is replaced by a cytokine. In contrast to toxins, cytokines are often proteins endogenously produced in man. If both the antibody and cytokine are of human origin, then no foreign proteins are introduced which could provoke an antibody response from the host immune system when the drug targeting preparation is clinically applied. 

Damle NK, Frost P. Antibody-targeted chemotherapy with immunoconjugates of calicheamicin. Curr Opin Pharmacol 20(B 3 386-90. 

Green SK, Francia G, Isidore C et al (2004) Antiadhesive antibodies targeting E-cadherin sensitize multicellular tumor spheroids to chemotherapy in vitro. Mol Cancer Ther 3 149-159... 

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