Part Two: Targeting Signal Transduction with Antibodies
Neha Vapiwala, MD and Geoffrey Geiger, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: September 13, 2010
To begin the second section of our examination of targeted therapies, we will transition from small molecule tyrosine kinase inhibitors (TKIs) to antibody-based targeted therapies. Please feel free to refer as needed to Part One, which presented the basic science principles behind targeted therapies and outlined the major classes of targeted therapies. Remember that the drugs have both generic and trade names, but we will use primarily the generic name in the following discussions. Table 2 contains the current FDA approved anticancer antibodies and will be a useful reference throughout this section.
Antibody therapy ultimately shares many targets common with the TKIs. To briefly review, antibodies are also known as immunoglobulins and are found in human blood. Their chief role is to identify and eliminate foreign cells such as bacteria and viruses. Although the basic structure of all antibodies is very similar, a region at the end of the protein is extremely variable, allowing for the recognition of millions of different targets, which are known as antigens. The unique part of the antigen recognized by an antibody is known as an epitope, which allows for a highly specific association with the antibody. Natural immunoglobulins are released by blood cells known as plasma cells, which are differentiated B cells. Although they are source of antibodies, plasma cells are also important because they can become cancerous (e.g., multiple myeloma). Normal plasma cells, once introduced to a specific stimulus, can churn out antibodies
capable of causing cell death through several mechanisms, including: complexing with the target, blocking receptors, activating a cell killing system known as the complement pathway or by directly killing cells through a process called antibody-dependent cell-mediated cytotoxicity (ADCC). Understanding these individual processes is not critical to our discussion on antibody therapies; suffice it to say that if you can target a cancer cell antigen with an antibody, you have a chance of killing that cancer cell.
In order to produce antibodies for oncological (and more generally, medicinal uses), they must be produced in large quantities in a laboratory and all must be designed to target the same antigen. Antibodies produced for medical uses may be mouse antibodies, human antibodies or a combination known as a chimeric antibody, which refers to the fact that the antibody produced is a hybrid of a human and a mouse antibody. We will also encounter the term 'humanized' which refers to antibodies whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans in an effort to reduce the likelihood of an undesirable reaction. However, production of these antibodies is technically more difficult than producing mouse antibodies. Chimeric antibodies represent a compromise between the two, where the mouse portion is minimized by hybridizing it to a human antibody, which may reduce the likelihood of the formation of human anti-mouse antibodies or infusional reactions. In general, chimeric antibodies are approximately 65% human, humanized antibodies are 95%, and human antibodies are 100%. The type of antibody can typically be deciphered from the generic drug name: -momab (murine), -ximab (chimeric), -zumab (humanized), or -mumab (human).
The following table lists the currently FDA approved antibodies used in the treatment of cancer. You may notice that these agents all have a single target as opposed to many of the TKIs, which possess multiple targets. Because of the highly specific nature of antibody-antigen associations, it is only possible for a single antibody to have a single target (i.e., every lock is unique and requires a specific key and no key can be used in two different locks). In the following section, our emphasis is on FDA approved indications only, as many of these agents are being tested in trials in other cancers, but are beyond the scope of this review.