Targeted Delivery of Neutralizing Anti-C5 Antibody to Renal Endothelium Prevents Complement-Dependent Tissue Damage

Abstract

Complement activation is largely implicated in the pathogenesis of several clinical conditions and its therapeutic neutralization has proven effective in preventing tissue and organ damage. A problem that still needs to be solved in the therapeutic control of complement-mediated diseases is how to avoid side effects associated with chronic neutralization of the complement system, in particular, the increased risk of infections. We addressed this issue developing a strategy based on the preferential delivery of a C5 complement inhibitor to the organ involved in the pathologic process. To this end, we generated Ergidina, a neutralizing recombinant anti-C5 human antibody coupled with a cyclic-RGD peptide, with a distinctive homing property for ischemic endothelial cells and effective in controlling tissue damage in a rat model of renal ischemia/reperfusion injury (IRI). As a result of its preferential localization on renal endothelium, the molecule induced complete inhibition of complement activation at tissue level, and local protection from complement-mediated tissue damage without affecting circulating C5. The ex vivo binding of Ergidina to surgically removed kidney exposed to cold ischemia supports its therapeutic use to prevent posttransplant IRI leading to delay of graft function. Moreover, the finding that the ex vivo binding of Ergidina was not restricted to the kidney, but was also seen on ischemic heart, suggests that this RGD-targeted anti-C5 antibody may represent a useful tool to treat organs prior to transplantation. Based on this evidence, we propose preliminary data showing that Ergidina is a novel targeted drug to prevent complement activation on the endothelium of ischemic kidney.

Complement Therapeutics in the Multi-Organ Donor: Do or Don't?

“…Rats received Ergidina 45 min before ischemia and were sacrificed at day 1 or day 4. Ergidina preserved renal function, prevented tissue injury at glomerular and tubular level and prevented C9 deposition in the kidneys at both day 1 and day 4 (49).…”

The Dual Role of the Liver in Nanomedicine as an Actor in the Elimination of Nanostructures or a Therapeutic Target

“…It is the case of an anti-C5 fused to a synovial tissue homing peptide, capable to block the C5 of the complement system specifically into the inflamed synovial tissue [116,117]. Using the same strategy, the same scFv-Fc has been fused to the RGD peptide in order to specifically block the complement system onto the 6 Journal of Oncology endothelium of inflamed kidneys [118]. Following the rationale to produce an antibody with a double specificity, bispecific antibodies have been generated.…”

The complex functioning of the complement system in xenotransplantation

“…Ergidina, a neutralizing recombinant anti-C5 antibody, protected rat kidneys from IRI by binding to injured endothelium. 195 The glycocalyx has been proven to be critical for protecting endothelial cells from activation during xenotransplantion. 196,197 The application of heparin onto mesenchymal stem cells, 198 or endothelial cells, 174 which would help to avoid or mitigate the shedding of the glycocalyx on the cell surface, may inhibit complement activation and improve graft cell viability.…”

“…For example, CR2‐complement inhibitor fusion proteins (CR2‐FH, CR2‐Crry, and CR2‐CD59) make local targeting feasible. Ergidina, a neutralizing recombinant anti‐C5 antibody, protected rat kidneys from IRI by binding to injured endothelium . The glycocalyx has been proven to be critical for protecting endothelial cells from activation during xenotransplantion .…”