**8.5. Eculizumab (Terminal complement inhibition with eculizumab)**

Almost all episodes of AMR are accompanied by evidence of early complement activation as demonstrated by C4d staining of the peritubular capillaries (Burns et al., 2008). However, the exact role of complement in the pathogenesis of AMR is unclear. Eculizumab is a humanized monoclonal antibody with high affinity for C5 and thus blocks the activation of terminal complement. Eculizumab is approved by the FDA for the treatment of paroxysmal nocturnal hemoglobinuria. Locke et al. (Locke et al., 2009) reported the successful treatment of a patient with severe AMR using eculizumab. Stegall and colleagues reported their initial experience with eculizumab treatment at the time of transplant showing that blockade of terminal complement prevented the development of AMR in patients who developed high levels of DSA post transplant (Stegall et al., 2009). Stegall et al also examined the efficacy of eculizumab in the prevention AMR in sensitized renal transplant recipients with a positive crossmatch against their living donor (Stegall et al., 2011). The incidence of biopsy-proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange-based protocol without eculizu‐ mab. The incidence of AMR was 7.7% in the eculizumab group compared to 41.2% in the control group (P = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with plasma exchange reducing the need for splenectomy. On 1-year protocol biopsy, transplant glomerulopathy was found to be present in 6.7% eculizumab-treated recipients and in 35.7% of control patients (P = 0.044).

Taken together, these studies suggest that terminal complement activation may play a critical role in the pathogenesis of early AMR. Thus, eculizumab may provide an attractive approach to the prevention of AMR.

#### **8.6. Future therapies with new targets**

#### *8.6.1. B cells*

Memory B cells are heterogeneous but have cell-surface markers (CD24, CD27, CD43 and CD79b) that are potential therapeutic targets (McHeyzer-Williams & McHeyzer-Williams, 2005). B cells also express TACI (transmembrane activator and calcium-modulating cyclophi‐ lin-ligand interactor), BCMA (B-cell maturation antigen) and BAFF receptor (B-cell-activating factor receptor), all of which are members of the TNF-receptor family that are triggered by the ligands BAFF and APRIL (a proliferation inducing ligand), which are expressed at the cell surface of DCs (Craxton et al., 2003). A soluble TACI–immunoglobulin fusion protein blocks B-cell development by inhibiting the interaction between B cells and DCs (Gross et al., 2001). These cell-surface markers might be useful targets to prevent the development of B cells into plasma cells.

### *8.6.2. Plasma cells*

some inhibition are encouraging, the lack of controls is a major limitation in assessing true efficacy. In addition, since even successfully treated AMR can still result in the development of chronic transplant glomerulopathy, the prevention of AMR might be a more important goal

Almost all episodes of AMR are accompanied by evidence of early complement activation as demonstrated by C4d staining of the peritubular capillaries (Burns et al., 2008). However, the exact role of complement in the pathogenesis of AMR is unclear. Eculizumab is a humanized monoclonal antibody with high affinity for C5 and thus blocks the activation of terminal complement. Eculizumab is approved by the FDA for the treatment of paroxysmal nocturnal hemoglobinuria. Locke et al. (Locke et al., 2009) reported the successful treatment of a patient with severe AMR using eculizumab. Stegall and colleagues reported their initial experience with eculizumab treatment at the time of transplant showing that blockade of terminal complement prevented the development of AMR in patients who developed high levels of DSA post transplant (Stegall et al., 2009). Stegall et al also examined the efficacy of eculizumab in the prevention AMR in sensitized renal transplant recipients with a positive crossmatch against their living donor (Stegall et al., 2011). The incidence of biopsy-proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange-based protocol without eculizu‐ mab. The incidence of AMR was 7.7% in the eculizumab group compared to 41.2% in the control group (P = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with plasma exchange reducing the need for splenectomy. On 1-year protocol biopsy, transplant glomerulopathy was found to be present

in 6.7% eculizumab-treated recipients and in 35.7% of control patients (P = 0.044).

Taken together, these studies suggest that terminal complement activation may play a critical role in the pathogenesis of early AMR. Thus, eculizumab may provide an attractive approach

Memory B cells are heterogeneous but have cell-surface markers (CD24, CD27, CD43 and CD79b) that are potential therapeutic targets (McHeyzer-Williams & McHeyzer-Williams, 2005). B cells also express TACI (transmembrane activator and calcium-modulating cyclophi‐ lin-ligand interactor), BCMA (B-cell maturation antigen) and BAFF receptor (B-cell-activating factor receptor), all of which are members of the TNF-receptor family that are triggered by the ligands BAFF and APRIL (a proliferation inducing ligand), which are expressed at the cell surface of DCs (Craxton et al., 2003). A soluble TACI–immunoglobulin fusion protein blocks B-cell development by inhibiting the interaction between B cells and DCs (Gross et al., 2001).

**8.5. Eculizumab (Terminal complement inhibition with eculizumab)**

of these types of therapies.

432 Current Issues and Future Direction in Kidney Transplantation

to the prevention of AMR.

*8.6.1. B cells*

**8.6. Future therapies with new targets**

Normal plasma cells express little or no CD20 and are therefore resistant to rituximabmediated depletion. Several cell-surface molecules that are expressed by plasma cells might be considered as drug targets — syndecan-1 (CD138), CD38, α4β1-integrin (CD49d–CD29) and CXC-chemokine receptor 4 (CXCR4) — although none of these is en‐ tirely plasma-cell specific. Plasma-cell longevity is thought to be an extrinsic phenomen‐ on that is mediated by survival signals delivered by bone-marrow stromal cells (Colvin & Smith, 2005). Because the transcription factors BLIMP1 (B-lymphocyte-induced matura‐ tion protein 1) and XBP1 (X-box-binding protein 1) (as well as the repression of PAX5, paired box gene 5) are required to maintain plasma-cell function, their inhibition might result in the loss of plasma-cell function (Shapiro-Shelef & Calame, 2005).

#### *8.6.3. Complement antagonists*

Complement antagonists could prevent the acute pathological effects of complement activa‐ tion. For example, soluble CR1 delays antibody-mediated rejection in xenograft models but is insufficient to prevent graft rejection completely (Azimzadeh et al., 2003). Other complement antagonists, such as C5-specific antibody, which blocks activation of C5 and formation of both C5a and the MAC, are in ongoing evaluation. Transgenic expression of human complementregulatory proteins (DAF and CD59) in pigs has shown potency for preventing xenograft rejection (Menoret et al., 2004), but the relevance of these studies to allografts needs to be extended and tested.
