Anti-CEACAM5 monoclonal antibody, clone UFU3

Background: Natural killer (NK) cells are essential to innate immunity and participate in cancer immune surveillance. Heterophilic interactions between carcinoembryonic antigen (CEA) on tumor cells and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) on NK cells inhibit NK cell cytotoxicity against tumor cells. NEO-201 is a humanized IgG1 monoclonal antibody that recognizes members of CEACAM family, expressed specifically on a variety of human carcinoma cell lines and tumor tissues. This investigation was designed to determine whether the binding of NEO-201 with CEACAM5 on tumor cells can block the CEACAM5/CEACAM1 interaction to restore antitumor cytotoxicity of NK cells. Materials and Methods: In vitro functional assays, using various human tumor cell lines as target cells and NK-92 cells as effectors, were conducted to assess the ability of NEO-201 to block the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to enhance the in vitro killing of tumor cells by NK-92. NK-92 cells were used as a model of direct NK killing of tumor cells because they lack antibody-dependent cellular cytotoxicity activity. Results: Expression profiling revealed that various human carcinoma cell lines expressed different levels of CEACAM5(+) and NEO-201(+) cells. Addition of NEO-201 significantly enhanced NK-92 cell cytotoxicity against highly CEACAM5(+)/NEO-201(+) expressing tumor cells, suggesting that its activity is correlated with the level of CEACAM5(+)/NEO-201(+) expression. Conclusions: These findings demonstrate that NEO-201 can block the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to reverse CEACAM1-dependent inhibition of NK cytotoxicity.

This trial determined the pharmacokinetics, dosimetry, and dose-limiting toxicity of Y-90-hMN-14 IgG (humanized anticarcinoembryonic antigen [CEA, or CEACAM5] monoclonal antibody; labetuzumab), combined with doxorubicin and peripheral blood stem cell (PBSC) support in advanced medullary thyroid cancer (MTC) patients. Methods: Fifteen patients received an infusion of In-111-hMN-14 IgG. One to 2 wk later, 14 patients received 90Y-hMN-14 IgG, starting at 740 MBq/m(2), followed 24 h later with a fixed intravenous bolus dose of doxorubicin (60 Mg/m(2)). Preharvested PBSCs were reinfused when the Y-90 activity in the body was <= 111 MBq/m(2). Results: The mean red marrow dose estimated for the 90Y-hMN-14 IgG was 1.65 +/- 0.59 mGy/MBq (n = 11), with normal organs ranging from similar to 2.3 to 4.4 mGy/MBq. Eighty percent of all known lesions (125/156), including 78 of 79 bone and 16 putatively occult lesions, were targeted. The average radiation dose to the tumor was 15.1 +/- 10.8 mGy/ MBq (55.8 39.8 cGy/mCi) Y-90-hMN-4 IgG (n = 29 tumors in 8 patients), with a majority of the lesions receiving > 2,000 cGy at an administered dose of <= 1,480 MBq/m(2). The average tumor-to-red marrow, tumor-to-liver, tumor-to-lungs, and tumor-to-kidneys ratios were 15.0 +/- 11.0, 5.1 +/- 3.6, 6.9 +/- 6.1 and 9.0 +/- 8.7, respectively. Cardiopulmonary toxicity was dose limiting at 1,850 MBq/m(2). Minor responses were noted in 2 patients and 1 patient had a partial response (68% reduction in local and hepatic metastatic disease). Conclusion: This treatment combination was well tolerated with complete recovery of blood counts and reversible nonhematologic toxicities at the maximum tolerated dose of 1,480 MBq/m(2). Evidence of antitumor response in these patients with advanced cancer was modest, but encouraging; this type of treatment may be more successful if applied to more limited, earlier-stage disease.