The Inhibitory Effect of CD46, CD55, and CD59 on Complement Activation After Immunotherapeutic Treatment of Cervical Carcinoma Cells with Monoclonal Antibodies or Bispecific Monoclonal Antibodies

Abstract

SUMMARY:The role of membrane-bound complement regulatory proteins (mCRP) in the protection of tumor cells in vivo against elimination by the immune system is still unknown. In this study the effect of expression of these mCRP by cervical cancer cells was investigated. In situ expression of mCRP was observed on cervical carcinomas, normal cervical epithelial cells, and the surrounding stroma. Deposition of C3 and C5b-9 was sporadically found on the tumor cells and the surrounding stroma. A low expression of CD46 was statistically significantly associated with deposition of C3. Comparable expression patterns were shown on primary cervical tumor cell suspensions. A relatively high deposition of C4c was found on these tumor cells, indicating classical pathway activation. Furthermore, it was demonstrated that CD55 and CD59 were the most potent inhibitors of C3 deposition and classical pathway-mediated lysis, respectively, on cervical cancer cell lines. The feasibility of increasing complement activation at the tumor cell membrane surface was demonstrated with an anti-HLA Class I*anti-CD55 bispecific mAb. The potential immunotherapeutic applicability was investigated with both anti-G250*anti-CD55 and anti-Ep-CAM*anti-CD55 bispecific mAbs. An approximate 2-fold increase in C3 deposition, compared with the parental anti-Ep-CAM mAb, was attained with an anti-Ep-CAM*anti-CD55 bispecific mAb when the tumor-associated antigen was expressed in sufficient amounts. These results demonstrate that when tumor-associated antigens are expressed in adequate amounts, bispecific mAbs in vivo may be potent immunotherapeutic agents to enhance an inflammatory reaction at the tumor site. (Lab Invest 2002, 82:483-493).

The dual role of complement in cancer and its implication in anti-tumor therapy

“…This approach is aiming at combining the tissue-specificity of an anti-tumor mAb together with the CDC effects of an anti-CRP mAb. Such antibodies against Crry, CD59 and CD55 have shown promising results (118,(128)(129)(130)(131).…”

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

“…115 CVF and C3b conjugated mAbs targeting the carcinoma antigen EpCAM-mediated higher C3 deposition and CDC of the colorectal carcinoma cell lines in vitro. 88,89 The same group demonstrated that b-glucan as adjuvant to mAbs activates CR3 on effector cells and results in CDCC (reviewed in ref. 116).…”

“…In vitro data resulted in a 3-fold increase in complement activation. 88,90 The feasibility of this approach was tested in a rat model. In rodents, the expression of mCRPs is different compared with humans: CD46 and CD55 is mainly expressed in the testis, and an additional functional homolog Crry/p65, acting at the level of C3, was identified as the most important mCRP on tumor cells in rats.…”

Systematic Immunohistochemical Analysis of the Expression of CD46, CD55, and CD59 in Colon Cancer

“…The use of bispecific mAbs that could specifically target mCRPs of cancer cells provides promising future results for mCRP-based immunotherapy. [23][24][25] Selectively down-regulating mCRP expression in tumors using cytokines or drugs other than antibodies may be another option because mCRPs expressed by colon cancer cells were reported to be regulated by tumor necrosis factor a, interleukin 1b, and interferon c. 26,27 In addition, by evaluating the expression of mCRPs, it may be possible to determine whether a patient is suitable for immunotherapy and to predict the response rate to treatment. Monitoring mCRP expression during the course of colon cancer could be important for evaluating disease progression and prognosis.…”