Systemic lupus erythematosus (SLE) is a chronic autoimmune disease mainly affecting women of childbearing age. It is estimated that, in the USA, up to 275,000 adult women suffer from SLE [1]. The disease involves different organs, but immune complex glomerulonephritis most strikingly influences the course of SLE. Ten to thirty percent of patients with lupus nephritis progress to end-stage renal disease (ESRD) resulting in hemodialysis or kidney transplantation [2]. Due to the application of immunosuppressive drugs, the survival of patients with lupus-associated glomerulonephritis increased from a 5-year survival of 44 % in the 1950s to a 10-year survival of 88 % recently [3]. Despite these advances in the treatment of SLE, the life expectancy of patients with lupus and renal damage was recently demonstrated to be 23.7 years shorter compared to the general population [4]. Moreover, the incidence of ESRD associated with lupus nephritis has not decreased over the last years [5], indicating that current medication is insufficient to treat lupus nephritis.
Unselective immunosuppressive drugs remain the central strategy to control lupus nephritis. Medication consists of an induction therapy with cyclophosphamide and prednisolone or mycophenolate mofetil, followed by a maintenance therapy with azathioprine or mycophenolate mofetil [6, 7]. Major side effects of this medication are infections, and they bear the risk of malignancies whereupon cyclophosphamide also causes amenorrhea [8–10]. Furthermore, none of the newly developed biological agents such as rituximab, ocrelizumab, atacicept, or abatacept demonstrated beneficial effects in patients with active lupus nephritis [11–15]. Two other biologicals reached statistical significance for the improvement of moderate to severe forms of SLE. However, the benefit of belimumab and tabalumab were modest [16, 17], the “number needed to treat” was high, and other phase III studies hardly reproduced the first results [18, 19].
The precise mechanism for the pathogenesis of SLE is unknown. Therefore, no targeted therapies beside immunosuppression exist so far. However, a potentially targeted therapy for SLE was suggested by a new finding from our group which was generated by serendipity. We demonstrated that the topoisomerase I (topo I) inhibitor irinotecan efficiently suppressed murine lupus nephritis in New Zealand Black/New Zealand White (NZB/NZW) mice [20–22]. It was the first time that topo I was linked to the treatment of lupus nephritis.
Topo I is ubiquitously expressed and highly conserved [23, 24]. Its major function is the relaxation of supercoiled DNA in order to release torsional stress from DNA occurring during replication and transcription. To mediate DNA relaxation, topo I binds to DNA and cleaves one DNA strand, subsequently allowing the rotation of the cleaved strand around the other in a controlled reaction [25]. Afterwards, the nicked strand is re-ligated by topo I restoring intact double-stranded (ds)DNA in a relaxed state.
Inhibitors of topo I stabilize a normally very transient catalytic intermediate in which topo I is bound to one strand of the DNA, known as the topo I cleavable complex. When the cleavable complex is stalled by topo I inhibitors, re-ligation of the DNA is impossible [26]. The consequence of prevented re-ligation may vary; in proliferating cells, the stalled topo I cleavable complex can collide with replication forks leading to unrepairable DNA double strand breaks and apoptosis [27, 28]. For this reason, topo I inhibitors, like camptothecin and its synthetic derivative irinotecan, are widely used as anticancer drugs for several types of tumors [29]. In non-dividing cells, the treatment with topo I inhibitors results in the production of single-stranded (ss)DNA breaks reducing the replication capacity of a cell, although this is not lethal [26]. In addition to the induction of ssDNA and dsDNA breaks, topo I inhibitors were shown at least in vitro to inhibit DNA relaxation [30, 31].
In our first experiments, we applied concentrations of irinotecan that were similar to those used for chemotherapy in humans [20]. Although irinotecan reversed established lupus nephritis, there have been some concerns about using yet another chemotherapeutic for the treatment of SLE in predominantly young women. However, subsequent experiments by our group demonstrated that much lower dosages were still efficient to suppress SLE. We ended up with a dose more than 50 times lower than the dose used for chemotherapy in humans, which still enabled the successful treatment of established lupus nephritis in NZB/NZW mice [21]. These extremely low concentrations guided us to the hypothesis that inhibition of topo I might be a targeted therapy for SLE. While a profound immunosuppression was ruled out [20–22], we hypothesized in the beginning that induction of ssDNA breaks as a consequence of topo I inhibition is the underlying mechanism [32]. However, later we found that topo I alone increased binding of anti-dsDNA antibodies [21, 22] supposing that DNA relaxation is critically involved in the pathogenesis of SLE.
All previous experiments using irinotecan for the treatment of SLE were performed in NZB/NZW mice. To provide more evidence for first clinical trials treating human SLE we had to rule out that the demonstrated effects of irinotecan are restricted to NZB/NZW mice. We therefore introduced the MRL/lpr mouse model which is characterized by a fast and severe disease progression involving fatal glomerulonephritis, vasculitis, skin lesions, and massive lymphadenopathy [33, 34]. In these mice, we tested whether irinotecan has similar beneficial effects on lupus-like disease as shown before in NZB/NZW mice.