Antibody Drug and Radionuclide Conjugates for GI Cancers

Abstract

In the mid-1980’s, after it was found that patients rapidly developed neutralising antibodies to tumour-directed ‘therapeutic mouse antibodies’, the concept of using these mouse antibodies to deliver cytotoxic therapeutics emerged. However, success was limited. Anti-mouse antibodies developed even with a limited number of infusions of the antibody-drug conjugates, and often the cytotoxic agents were released in the blood stream producing serious toxicities. The field of antibody-conjugates was quiet while technology for humanisation of mouse antibodies and the means of producing fully human antibodies evolved, and linker chemistry was developed, which allowed stable transport of antibody-conjugates to the target cells and release of the cytotoxic agent inside the target cells (Fig. 4.1) [1–3]. The first antibody-drug conjugate to reach Food and Drug Administration (FDA) approval in 2000 was gemtuzumab ozogamicin (Mylotarg), which targeted CD33 on the surface of acute myeloid leukaemia cells and delivered the potent cytotoxic agent, calicheamicin, inside the leukaemia cells. In 2010, gemtuzumab ozogamicin was withdrawn from the market after failing to produce sufficient efficacy in follow-up clinical trials [4]. Two antibody-drug conjugates (ADCs), trastuzumab emtansine (T-DM1; Kadcyla) and brentuximab vedotin (SGN-35; Adcetris) reached FDA approval in 2014 and 2011 for treatment of metastatic breast cancer and refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively [5, 6]. Approximately 50 ADCs have reached clinical trial to date, with more than 40 in trials currently and nearly 20 in, or having completed Phase 2 clinical trials (Table 4.1). The ADCs under investigation target haematological and solid tumours [7, 8]. The current chapter focuses on those that may be useful in the treatment of GI cancers.