The overall objective of this Program Project Grant is to define the clinical role of radiolabeled, genetically engineered antibodies directed against anti-carcinoembryonic antigen (CEA). During the previous granting period a chimeric version of a high affinity anti-CEA antibody was evaluated in clinical imaging and early therapy trials. The imaging trials were conducted with an Indium-111 labeled product. The therapy studies were performed with an Yttrium-90 labeled product. These studies will be extended using a I-123 labeled F(ab')2. This should allow imaging of hepatic lesions as well as reduce the time for optimal imaging. Following these studies we will evaluate a I-123 labeled genetically engineered fragment of 80,000 daltons consisting of two single chain antibodies fused to a human hinge region and then terminated in human CH3 domains. Animal studies have shown this to be a human hinge region and then terminated in human CH3 domains. Animal studies have shown this to be a superior reagent. Subsequent imaging trials will focus on novel constructs being developed under Project 2 (Bioengineered Antibodies). The therapy aspects of this proposal will focus on completing Phase I studies with 90Y-antibodies in breast cancer patients in the setting of autologous stem cell support as well as continued studies of the same reagent administered intraperitoneally (IP) in patients with CEA positive intraperitoneal disease. A Phase I/II study utilizing a novel DOTA chelation agent will then document response rate. From these Phase I/II studies the basis for subsequent clinical trials utilizing concomitant chemotherapy will be established. the next round of therapy trials will therefore focus on using 5-FU with 90Y-antibody in patients with metastatic colorectal cancer as well as IP studies with IUDR and 90Y labeled anti-CEA antibodies. The ABMT breast trial will be followed with a trial using the 90-Y-antibody with 5-FU/leucovorin/cisplatinum. In this way we will exploit the known radioenhancing properties of these chemotherapeutic agents, allowing us to proceed with therapeutic studies more likely to produce significant tumor responses. The clinical studies will be enhanced by the development of novel therapeutic reagents in the other two projects. Project 2 will pursue a humanized, less immunogenic chimeric antibody, a series of novel engineered minibody constructs, and two bioactive antibody/ lymphokine fusion proteins. Project 3 (Antibody Chelates and Conjugates) will provide the net generation of chelates and conjugates. Macrocycle chelates optimized for heavy radiometal binding and site specific modification will be the focus. This program Project is supported by six experienced Cores, providing the necessary reagents and support to carry out the basic research and translational clinical studies.
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