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

Abstract

A panel of four murine monoclonal antibodies apparently directed against three distinct epitopes of carcinoembryonic antigen (CEA) was conjugated via oxidized carbohydrate groups to 4-desacetylvinblastine-3-carboxyhydrazide. The resulting antibody-vinca conjugates were evaluated for antitumor activity against 2-9-day-established LS174T human colorectal carcinoma xenografts. The antibodies (immunoglobulin G, IgG) employed in this study were 11.285.14 (IgG1), 14.95.55 (IgG2a), CEM231 (IgG1), ZCE025 (IgG1). Additive immunofluorescence studies indicated that CEM231 and ZCE025 recognized the same or a closely related epitope(s) on CEA which was distinct from the two epitopes bound by 11.285.14 and 14.95.55. The in vivo antitumor efficacy studies demonstrated that chemoimmunoconjugates prepared from 14.95.55 and ZCE025 were more active than the conjugates constructed from the 11.285.14 and CEM231 antibodies. The 14.95.55 and ZCE025 immunoconjugates were also more efficacious than free drug or drug conjugated to irrelevant murine IgG. The presence of increased carbohydrate content on the light chain of ZCE025 may have been responsible for the ability to construct ZCE025-vinca conjugates with about twice the drug content (approximately 10 mol of vinca/mol of IgG) than was achieved with the other antibodies. The highly conjugated form of ZCE025 demonstrated similar efficacy but was much less toxic than a ZCE025 conjugate containing 5 mol of vinca/mol of IgG. These data indicated that significant differences existed in the ability of monoclonal antibodies to target a cytotoxic agent for effective antitumor activity even when the immunoconjugates recognized the same antigen or even the same or closely related antigen epitope(s). Furthermore, these differences could not have been identified without extensive in vivo evaluation for antitumor efficacy.

Novel Acid Labile COL1 Trityl-Linked Difluoronucleoside Immunoconjugates: Synthesis, Characterization, and Biological Activity1

“…The nature of the antigen, for example shedding which would lead to circulating levels of CEA, in the HC1 tumor model was not examined in these studies. Selective targeting, however, has previously been achieved using a different mAb drug conjugate that also recognizes CEA (38). The release studies indicate that conjugate 3 requires an acidic environment to release free drug 1; however, the pH of HC1 tumors was not determined due to the complexity encountered in measuring tumor tissue versus adjacent normal tissue as well as extracellular (pHe) versus intracellular (pHi).…”

Antibody–Drug Conjugates for Cancer Treatment

“…The early work in the field of ADCs sought to increase the specificity of existing chemotherapeutic drugs, such as the vinca alkaloids (11) and doxorubicin (12). However, the results of clinical trials of these conjugates were disappointing (e.g., 13,14), and by the early 1990s there was a greater appreciation of the challenges that the in vivo biodistribution properties of antibodies imposed on ADC design.…”

Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193- N -Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts

“…Multiple conjugates of antibodies and chemotherapeutic agents (immunoconjugates) have a proven ability to inhibit growth of a host of xenografted tumors. Some examples of targeted TAAs are Her-2/neu (13,14), prostate stem cell antigen (15), mucine type glycoproteins (16), epidermal growth factor receptor (17), carcinoembryonic antigen (18), CD22 (19), and Lewis y (Le y ; 20). To achieve a cytotoxic effect, antibodies against these surface antigens were conjugated to pseudomonas exotoxin (14), maytansin (15,16), calicheamicin (19), Rnase (17), Vinca alkaloids (18), or doxorubicin (20).…”