Modulation of mCRPs for Immunotherapy

Since mCRPs can prevent efficient complement activation, inhibit complement-mediated killing mechanisms such as CDC, ADCC, CR3-DCC, and also down-regulate effector T cell responses, it is therefore hypothesized that blockade or neutralizing mCRPs would significantly improve anti-tumor mAb-based tumor immunotherapy or vaccine-mediated anti-tumor immune responses. These strategies include neutralizing mAbs against mCRPs, small interfering RNAs or anti-sense oligos to knockdown mCRPs, utilization of chemotherapeutic drugs or cytokines to downregulate mCRPs, and a recently proposed new approach for suppression of expression of membrane-bound complement regulator (mCR) genes.

5.1 Neutralizing mAbs

Specific inhibition of mCRP activity has been achieved with blocking mAbs against CD46, CD55, and CD59. In most of in vitro studies, anti-mCRP blocking mAbs have successfully demonstrated the enhancement of susceptibility of tumor cells to complement-mediated killing mechanisms. For example, neutralization of CD55 with blocking mAb in Burkitt lymphoma cells (Kuraya et al. 1992), leukemia cells (Jurianz et al. 2001), melanoma cells (Cheung et al. 1988), and breast cancer cells (Madjd et al. 2004) can significantly increase their sensitivity to complement-mediated killing. Similarly, blockade of CD59 with neutralizing mAb significantly enhances efficiency of complement-mediated lysis to neutroblastoma cells (Chen et al. 2000), leukemia cells (Jurianz et al. 2001), breast (Ellison et al. 2007), ovarian (Donin et al. 2003), renal (Gorter et al. 1996), and prostate carcinoma cells (Jarvis et al. 1997). Blocking mAb for CD46 is controversial in the in vitro studies. In renal carcinoma, blocking CD46 did not significantly affect complement sensitivity (Ajona et al. 2007). This may be related to a particular blocking mAb since inhibition of CD46 mRNA expression significantly increases complement-mediated lysis (Buettner et al. 2007).

Inhibition of mCRPs with neutralizing mAbs may also enhance ADCC effect via iC3b-CR3 interaction. Our recent study indicated that anti-CD55 blocking mAb, but not anti-CD46 blocking mAb, significantly enhanced iC3b deposition on tumors mediated by anti-her-2/neu mAb (Li et al. 2007). Although blocking anti-CD55 itself does not significantly increase the iC3b-CR3-mediated ADCC, enhanced iC3b deposition on tumors synergizes with yeast-derived p-glucan to elicit enhanced CR3-DCC in vitro. More importantly, in vivo administration with anti-CD55 mAb with p-glucan plus anti-her-2/neu mAb elicited tumor regression and long survival in animals bearing the previously resistant SKOV-3 human ovarian carcinoma. In addition, blocking anti-CD55 significantly led to C5a release and massive neutrophil influx within tumors.

However, one concern regarding use of anti-mCRP mAb blockade in vivo is widespread expression of mCRPs on normal tissues or cells such as red blood cells (Lublin and Atkinson 1989). This could potentially lead to hemolytic or vascular disease as a result of increased complement activation on normal cells or targeting by ADCC. This drawback may be overcome by using bi-specific mAb against tumor Ag with higher affinity and CD55 or CD59 with lower affinity (Gelderman et al. 2002a,b; Harris et al. 1997). A previous study has demonstrated that this strategy could specifically target tumor cells with minimally binding to normal cells and increase p-glucan mediated CR3-DCC (Gelderman et al. 2006). Indeed, bi-specific mAb to epithelial cell adhesion molecule (Ep-CAM) and Crry in rat has demonstrated a significant therapeutic efficacy for a rat colorectal cancer lung metastases model in vivo (Gelderman et al. 2004a). Moreover, a recent study showed that CD55 is highly expressed on tumor cells but not on non-neoplastic epithelia, suggesting that it might predominately target the tumor (Ravindranath and Shuler 2006).

5.2 Small Interfering RNAs or Anti-sense Oligos

Since the in vivo utilization of blocking mCRP mAbs could potentially cause undesirable adverse effects, novel strategies to block mCRPs on tumors have been developed. For example, using small interfering RNA (siRNA) technology, CD55 expression levels can be significantly downregulated in prostate cancer cells leading to a profound attenuation of overall tumor burden in vivo (Loberg et al. 2006). Similarly, CD46 siRNA downregulates CD46 expression on prostate cancer resulting in enhanced CDC in vitro (Buettner et al. 2007). Our recent study using CD59 siRNA showed that downregulation of CD59 on human ovarian carcinoma SKOV-3, non-small cell lung carcinoma NCI-H23, and breast carcinoma ZR-75-1 significantly enhanced their susceptibility to anti-tumor mAb and complement-mediated cell lysis (Yan R., et al. unpublished observations).

In addition to siRNAs, anti-sense phosphorothioate oligonucleotides (S-ODNs) are also used to knockdown mCRP expression on tumor cells (Zell et al. 2007). Using S-ODNs for CD46 and CD55, the expression levels of these two molecules were significantly decreased in breast, lung, and prostate carcinoma. The inhibition of mCRPs on tumors led to enhanced CDC both for CD46 and CD55. In addition, C3 opsonization on CD46/CD55-deficient tumor cells was also significantly enhanced. Further in vivo study is needed to test the efficiency and potency of this strategy.

RNA interference (RNAi) can be induced by synthetic siRNA or by vector-driven expression of shRNA. Vectors are usually delivered by viruses resulting in incorporation of the vector into the host genome and a long-term gene silencing. However, this induces unwanted immune response and possible toxic effects. In contrast, siRNA provides a transient gene silencing solving the drawbacks with possible insertional mutagenesis and immune response induction. However, the major challenge is its delivery into cells in vivo and the faded silencing effect due to the high proliferation rate of tumors.

5.3 Chemotherapeutic Drugs

Interestingly, the chemotherapeutic drug fludarabine down-regulates CD55 expression on tumor cells (Di Gaetano et al. 2001). This may well explain the synergistic cytotoxicity of fludarabine and anti-CD20 mAb (rituximab) in a follicular lymphoma cell line (Di Gaetano et al. 2001). We also showed that Paclitaxel could significantly downregulate CD59 on human ovarian carcinoma and synergize with anti-her-2/neu mAb for tumor cytotoxicity (Yan et al. unpublished observation). Study with other chemodrugs is underway. This may be very important since many anti-tumor mAbs are used in combination with chemotherapeutic drugs. The right combination may lead to the maximum therapeutic outcomes.

5.4 Peptide Inhibitors of mCR Gene Expression

Recently we have proposed a new strategy for decreasing expression of mCRPs on tumor surface by downmodulating mCR gene expression (Donev et al. 2006). This can be achieved by targeting transcriptional regulators of the mCR genes. We showed that p53 is a potential target for modulation of expression of CD59 in neuroblastoma (Donev et al. 2006), a tumor type in which mutations in p53 are rare (Valsesia-Wittmann et al. 2004). However, in most other tumors, the DNA-binding domain of p53 is usually mutated (Greenblatt et al. 1994). Hence, p53 is unlikely to be involved in regulation of CD59 expression. Recently we identified another transcription factor involved in overexpression of CD59 in neuroblastoma. This is the neural-restrictive silencer factor (NRSF, REST), which is expressed as a truncated protein not only in neuroblastoma (Palm et al. 1999), but also in small cell lung carcinoma (Coulson et al. 2000) and colorectal cancer (Westbrook et al. 2005). We showed that the expression of this truncated isoform of REST is related to everexpression of CD59 in neuroblastoma and it can be targeted with peptides to sensitize tumor to CDC killing (Donev et al. unpublished data).

We believe that targeting both the mCR gene expression and the stability of synthesized RNA with peptide inhibitors and RNAi, respectively, will significantly decrease the number of mCRPs on tumor surface, resulting in effective CDC killing.

6 Concluding Remarks

It is becoming clear that the evolutionarily ancient complement system can be manipulated to substantially contribute to our current state of the art oncology treatment, particularly to anti-tumor mAb therapy. However, upregulation of mCRPs on tumors imposes an obstacle to maximize the therapeutic efficacy mediated by anti-tumor mAbs or tumor vaccines. Such obstacles may be overcome by the co-administration of neutralizing anti-mCRP mAbs or siRNAs or antisense Oliges to achieve this goal. Indeed, many in vitro studies have demonstrated the synergistic effect when anti-tumor mAb is used in combination with blocking mAbs for mCRPs or other approaches. However, their in vivo efficacy needs to be further investigated.

Acknowledgements

This work was supported by NIH/NCI RO1 CA86412, the Kentucky Lung Cancer Research Board, the James Graham Brown Cancer Center Pilot Project Program to J.Y. and by the MRC New Investigator Grant 81345 to R.D.

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