A fluorouridine‐anti‐CEA immunoconjugate is therapeutically effective in a human colonic cancer xenograft model

Abstract

5-fluorouridine (FUR), an antineoplastic agent, was site-specifically conjugated to the carbohydrate moiety of a anticarcinoembryonic antigen (CEA) monoclonal antibody (MAb) by using amino-dextran as the intermediate carrier. The final immunoconjugate contains approximately 30-35 molecules of FUR per molecule of immunoglobulin, has immunoreactivity retained as examined by flow cytometry, and is cytotoxic to the target cells as examined by 75selenomethionine incorporation studies. In the GW-39/nude mouse model, the conjugate remained efficient in targeting the human colonic tumor and possessed greater inhibitory growth effects on the subcutaneous tumor than free FUR or an irrelevant antibody conjugate. In addition, the reduced host toxicity of the conjugate may permit the use of this agent in a high-dose therapy of this tumor system.

Carboxymethyl dextran lactone: A preactivated polymer for amine conjugations

“…Using established carbodiimide coupling techniques we coupled 4-methoxybenzylamine to carboxymethyldextran (8). We were amazed, however, to observe that the degree of substitution determined by UV quantification (4) of our methoxybenzylamine chromophore was in substantial disagreement with the degree of substitution determined by another commonly-employed technique which uses the % nitrogen analysis to determine drug load (9), in our case 4-methoxybenzylamine content. High resolution 1H-NMR studies soon demonstrated that our carboxymethyldextran conjugate contained an appreciable amount of bound IV-acylurea derived from the carbodiimide.…”

Therapeutic monoclonals

“…In order to overcome the limitations caused by systemic toxicity, a number of chemotherapeutic agents, such as doxorubicin, bleomycin, chlorambucil, cisplatin, vinca alkaloids and mitomycin C, have been conjugated to tumour-specific MAbs. By using chimaeric antibodies in a number of animal studies and by developing methods that allowed more than one drug molecule to bind to the antibody, the number of the drug molecules targeted was increased without altering the MAbs' properties, thus achieving high rates of cures and decreasing the toxicity [44,45].…”

In vivo antitumor activity of a panel of four monoclonal antibody-vinca alkaloid immunoconjugates which bind to three distinct epitopes of carcinoembryonic antigen

“…The normal physiologic role of CEA is still unclear, but recent studies have identified it as an adhesion-related protein and a member of the immunoglobulin supergene family (3). mAbs directed against numerous epitopes of CEA have been characterized (4-11) and many papers have described the diagnostic and therapeutic potential of radio-, toxin-, and chemoimmunoconjugates constructed using anti-CEA mAbs (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). A number of recent publications have elucidated the potent in vivo antitumor activity of mAb-DAVLBHYD conjugates directed against various human solid tumor membrane antigens.…”