Gary Walsh
|
As of late 2004, 26 modern antibody-based therapeutic agents have been approved in the European Union and the US. Some 500
such products are currently in development, ensuring that the number of approved antibody-based products will increase substantially
over the coming years.
Traditionally, polyclonal antibodies have been used to induce passive immunity. These antibody preparations are made by extracting
human or animal serum exposed to the antigens of interest. Antibody preparations produced by such means are heterogeneous.
Antibody levels vary from bleed to bleed and, when the producer animal dies, so does the product source.
The mid 1970s development of hybridoma technology allowed production of large amounts of monospecific antibodies against virtually
any antigen of interest.1,2 This technique fuses a mouse-derived (murine), antibody-producing lymphocyte with a transformed (cancerous) myeloma cell.
A proportion of the daughter hybrid cells (hybridomas) continue to produce the murine antibody and also retain the immortal
character of the parent myeloma cell. The hybridoma can be stored in a viable state for years, providing an almost inexhaustible
seed supply of monoclonal antibody (MAb). The most striking attribute is that all the individual antibody molecules present
in a monoclonal antibody preparation are identical (See "Antibody Structure" box on page 2).
RCSB Protein Data Bank, 15c8, http://www.rcsb.org/pdb
|
MAbs initially found wide application as in vitro diagnostic reagents in immunoassays. Starting in the 1980s, several gained regulatory approval for in vivo use — either as therapeutic or diagnostic agents.3,4 The major target indication of modern antibody preparations is cancer, although several products aimed at additional indications
also have been approved (Table 1).
SPECIFIC SELECTIVITY
The binding of an antibody to the antigen against which it is produced is extremely specific. All human (and indeed other)
cells display a range of surface antigens. Some are found on a range of cell types, while others — termed unique surface antigens
(USAs) — are specific to a given cell type. Antibodies produced against unique surface antigens bind selectively to the surface
of these cells. In effect these antibodies are "magic bullets" capable of selectively targeting specific cell types such as
cancer cells, virally infected cells, or microbial cells at an infection site.
Antibodies generally display favorable safety profiles. Humanized antibodies (described below), in particular, are well tolerated
at high doses. Furthermore, engineered antibodies can be quite versatile. Slight changes in the six to ten amino acids within
the complementarity-determining region (Figure 1) can retarget the antibody, creating a new potential therapeutic. Common
drug development and manufacturing approaches can be employed to bring the product to market.
Figure 2. Antibody-Based Therapeutics (a) Antibodies bind selectively to specific cell types if they are raised against a
unique surface antigen (USA). (b) Effector molecules can be conjugated to the antibody. Radioactive tags are employed to either
detect or destroy the target cell. (c) Toxins can also be used as cytocidal agents. (d) Enzymes (E) can selectively convert
a harmless prodrug into a cytocidal agent at the cell surface.
|
Binding of an antibody to a cell surface can potentially trigger cellular destruction via immunological effector functions
associated with the antibody's Fc region (for example, phagocytic destruction and complement activation). Antibody-mediated cellular destruction generally
involves conjugating an antibody to a cytotoxic agent, usually a radionuclide, a toxin, or potentially an enzyme capable of
converting an inactive prodrug into an active cytocidal agent (Figure 2). The antibody delivers the cytocidal agent directly
to the surface of the target cell — and defines antibody-mediated cellular targeting.
ANTIBODY-MEDIATED CANCER DIAGNOSIS AND THERAPY
When a cell is transformed (becomes cancerous), it usually begins high-level expression of several genes that were previously
either unexpressed or expressed at extremely low levels. Some of the resultant proteins are found on the cell surface and
are termed tumor surface antigens (TSAs). TSAs potentially represent unique surface antigens, and antibodies raised against
specific TSAs are likely to be approved for oncological applications.
Several anti-TSA antibodies conjugated to radioactive tags have been approved for the detection and treatment of various cancers
(Table 1). Conjugation of radioactive tags to anti-TSA MAbs facilitates targeted tumor destruction via the ionizing effects
of radioactivity. 5
