Inhibiting the EGF family of receptor kinases

Xenografts are fragments of tumour tissue or suspensions of dissociated tumour cells, implanted or injected under the skin of female athymic (‘nude’) mice. These mice cannot reject the cancer cells and they serve a good in vivo model to study bioavailability, adverse affects, and efficiency of potential therapeutic compounds.

bullets. Their use in research and diagnostics has been widespread and extremely successful. So far, however, they have not lived up to their initial promise as therapeutic agents, particularly in the treatment of cancer. One important limiting factor is the incidence of anti-antibody immune responses.

Inhibitor monoclonal anti-ErbB1 antibodies were raised against partially purified receptors and also A431 cancer cells that over express the receptor.29 One of the clones, mAb225, formed the basis for the generation of a chimeric antibody named cetuximab (the ‘mab’ at the end of this made-up generic name tells you that the drug is a monoclonal antibody).30 This is a potent inhibitor of cancer cells that exhibit autocrine EGF-receptor activation and it has been applied in the treatment of colon cancer, often in combination with a topo-isomerase inhibitor.

A monoclonal antibody, mAb4D5, directed against ErbB223 formed the starting point for the generation of trastuzumab, used in the treatment of metastatic breast cancer. Over-expression of ErbB2 occurs in 25% of

human breast cancers, particularly the more aggressive cases having a poor prognosis. Its structure differs from the other EGF receptors in that it exists permanently in an open configuration31 and is unable to bind ligands: it

is a true orphan receptor. However, it does act as a coreceptor, dimerizing with the other members of this receptor family when they are activated by ligands. The antibody binds the membrane proximal domain of ErbB2 (Figure 23.3).32 When applied to transformed breast cells it activates the tumour-suppressing PI(3,4,5)P3 phosphatase PTEN.33 Among many other effects, it also induces expression of the cell cycle inhibitor p27KIP1 and the retinoblastoma-related protein p130. It diminishes surface expression of ErbB2, restores E-cadherin expression (cell–cell contact) and reduces the

release of the pro-angiogenic factor VEGF.34 Most importantly, it inhibits cell proliferation.

There are several mechanistic explanations that might account for these effects. Thus, the antibody could cross-link the receptor without inducing transphosphorylation. Also, it could stimulate receptor internalization or induce proteolytic cleavage of the extracellular region. The mechanism underlying its clinical efficacy remains unclear but, in view of experience derived from in vitro investigations, this is likely to be multifaceted.

It is important to recognize that antibodies bound to a cell surface have the inherent tendency to recruit immune effector cells that possess Fc-receptors (Fc RI, II, or III), such as macrophages and monocytes. These bind crosslinked Fc domains and so in this way antibodies may provoke cell-mediated cytotoxicity. This mechanism appears to be the cause of tumour regression in mouse xenograft models.34