RESUMEN
Carcinoembryonic antigen (CEA) is a classic tumor-specific antigen that is overexpressed in several cancers, including gastric cancer. Although some anti-CEA antibodies have been tested, to the best of our knowledge, there are currently no clinically approved anti-CEA antibody therapies. Because of this, we have created the novel anti-CEA antibody, 15-1-32, which exhibits stronger binding to membrane-bound CEA on cancer cells than existing anti-CEA antibodies. 15-1-32 also shows poor affinity for soluble CEA; thus, the binding activity of 15-1-32 to membrane-bound CEA is not influenced by soluble CEA. In addition, we constructed a 15-1-32-monomethyl auristatin E conjugate (15-1-32-vcMMAE) to improve the therapeutic efficacy of 15-1-32. 15-1-32-vcMMAE showed enhanced antitumor activity against gastric cancer cell lines. Unlike with existing anti-CEA antibody therapies, antitumor activity of 15-1-32-vcMMAE was retained in the presence of high concentrations of soluble CEA.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antígeno Carcinoembrionario/inmunología , Oligopéptidos/química , Neoplasias Gástricas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , RatonesRESUMEN
The immune system has two broad components-innate and adaptive immunity. Adaptive immunity becomes established only after the onset of hematopoiesis, whereas the innate immune system may be actively protecting organisms from microbial invasion much earlier in development. Here, we address the question of whether the innate immune system functions in the early-stage embryo, i.e., the blastocyst. The innate immune system was studied by using in vitro blastocyst models, e.g., embryonic stem (ES) and trophoblast stem (TS) cell cultures. The expression of Toll-like receptors (TLR)-2, -3, and -5 could be detected in both ES and TS cells. The expression of interferon (IFN)-ß was induced by the addition of polyinosinic:polycytidylic acid [poly(I:C)] in TS cells, but not ES cells, although TLR-3 was expressed at the same level in both cell types. In turn, ES cells responded to IFN-ß exposure by expressing IFN-induced anti-viral genes, e.g., RNA-dependent protein kinase and 2', 5'-oligoadenylate synthetase (OAS). Neither a reduction in ES cell proliferation nor cell death in these cultures was observed after IFN-ß stimulation. Furthermore, OAS1a expression was induced in ES/TS co-cultures after poly(I:C) stimulation, but was not induced when either cell type was cultured alone. In conclusion, TS cells react to poly(I:C) stimulation by producing IFN-ß, which induces IFN-inducible genes in ES cells. This observation suggests that the trophectoderm, the outer layer of the blastocyst, may respond to viral infection, and then induce anti-viral gene expression via IFN-ß signaling to the blastocyst inner cell mass.