SC-1
The human monoclonal antibody SC-1 was isolated from a patient with a diffuse-type adenocarcinoma of the stomach using somatic cell hybridization.
The immunoglobulin (Ig)M antibody SC-1 reacts specifically with diffuse- (70%) and intestinal-type (25%) gastric adenocarcinoma and induces apoptosis in vitro and in vivo.
The SC-1 receptor is CD55, a new 82 kd membrane-bound isoform of glycosylphosphatidylinositol (GPI)-linked (or decay-accelerating factor, DAF). CD55 is known to protect cells from lysis through autologous complement and is coexpressed with the ubiquitously distributed 70 kd isoform.
The SC-1-specific CD55 isoform is up-regulated shortly after antibody binding, followed by an internalization of the antibody/receptor-complex, whereas the membranous expression of wild-type CD55 remains unchanged.
The apoptotic process is marked by cleavage of cytokeratin 18 (CK18), indicating the involvement of caspase-6 (CASP6) in the apoptotic process. In contrast to other apoptotic pathways, a cleavage of poly(ADP-ribose)polymerase (PARP) is not observed.
The expression of the cell-cycle regulator c-myc becomes up-regulated, whereas expression of topoisomerase IIalpha is down-regulated.
Induction of apoptosis leads to an increase in the internal Ca(2+) concentration, which is not necessary for the apoptotic process but for the transport of newly synthesized SC-1-specific CD55 isoform to the membrane.
The human monoclonal antibody SC-1 induces apoptosis of stomach carcinoma cells and is currently used in a clinical Phase II trial.
Nude mice xenotransplantation data (15756455)
- Human gastric tumor specimens with positive expression of the SC-1 receptor were transplanted in nude mice with metastasizing gastric cancer.
- Animals receiving SC-1 had significantly fewer disseminated tumor cells (DTCs) than did control animals.
- None of the SC-1 mice had DTCs simultaneously in both blood and bone marrow versus four of the control animals.
- The reduction of DTCs in SC-1 animals was due to reduction in bone marrow, but not in blood.
- Treatment with SC-1 significantly reduced the number of DTCs in bone marrow in this animal model.
References
Illert B, Otto C, Vollmers HP, Hensel F, Thiede A, Timmermann W. Human antibody SC-1 reduces disseminated tumor cells in nude mice with human gastric cancer. Oncol Rep. 2005 Apr;13(4):765-70. PMID: 15756455
Hensel F, Hermann R, Brandlein S, Krenn V, Schmausser B, Geis S, Muller-Hermelink HK, Vollmers HP. Regulation of the new coexpressed CD55 (decay-accelerating factor) receptor on stomach carcinoma cells involved in antibody SC-1-induced apoptosis. Lab Invest. 2001 Nov;81(11):1553-63. PMID: 11706063
Hermann R, Hensel F, Muller EC, Keppler M, Souto-Carneiro M, Brandlein S, Muller-Hermelink HK, Vollmers HP. Deactivation of regulatory proteins hnRNP A1 and A2 during SC-1 induced apoptosis. Hum Antibodies. 2001;10(2):83-90. PMID: 11673663
Hensel F, Hermann R, Schubert C, Abe N, Schmidt K, Franke A, Shevchenko A, Mann M, Muller-Hermelink HK, Vollmers HP. Characterization of glycosylphosphatidylinositol-linked molecule CD55/decay-accelerating factor as the receptor for antibody SC-1-induced apoptosis. Cancer Res. 1999 Oct 15;59(20):5299-306. PMID: 10537313
Vollmers HP, Zimmermann U, Krenn V, Timmermann W, Illert B, Hensel F, Hermann R, Thiede A, Wilhelm M, Ruckle-Lanz H, Reindl L, Muller-Hermelink HK. Adjuvant therapy for gastric adenocarcinoma with the apoptosis-inducing human monoclonal antibody SC-1: first clinical and histopathological results. Oncol Rep. 1998 May-Jun;5(3):549-52. PMID: 9538151
Vollmers HP, Hensel F, Hermann R, Dammrich J, Wozniak E, Gessner P, Herrmann B, Zimmermann U, Muller-Hermelink HK. Tumor-specific apoptosis induced by the human monoclonal antibody SC-1: a new therapeutical approach for stomach cancer. Oncol Rep. 1998 Jan-Feb;5(1):35-40. PMID: 9458378
Vollmers HP, Dammrich J, Hensel F, Ribbert H, Meyer-Bahlburg A, Ufken-Gaul T, von Korff M, Muller-Hermelink HK. Differential expression of apoptosis receptors on diffuse and intestinal type stomach carcinoma. Cancer. 1997 Feb 1;79(3):433-40. PMID: 9028351
Vollmers HP, Dammrich J, Ribbert H, Wozniak E, Muller-Hermelink HK. Apoptosis of stomach carcinoma cells induced by a human monoclonal antibody. Cancer. 1995 Aug 15;76(4):550-8. PMID: 8625146
Vollmers HP, O?Connor R, Muller J, Kirchner T, Muller-Hermelink HK. SC-1, a functional human monoclonal antibody against autologous stomach carcinoma cells. Cancer Res. 1989 May 1;49(9):2471-6. PMID: 2706635