Soluble Complement Regulators: The Natural Therapeutic Targets
The complement system maintains tissue homeostasis and integrity, which initiates and coordinates immune reactions attacking and clearing tagged foreign cells and altered self cells, such as apoptotic particles. However, the activation of complement generates highly toxic products. And consequently, it needs to be precisely and tightly regulated by multiple inhibitors and regulators, including integral membrane proteins, surface-bound regulators, and soluble effectors, which are distributed in the body fluids and plasma.
Background
As dysregulation of the balance between complement activation products and regulators results in different autoimmune diseases, diverse complement regulators are considered as the natural modifiers, effectively preventing the complement system from attacking the host cells.
Research in early complement-directed drug discovery has further demonstrated that complement regulators, especially soluble complement regulators, are important therapeutic targets for autoimmune diseases.
About Soluble Complement Regulators
The first breakthrough was reached in complement-directed drug discovery with the expression of a soluble form of complement receptor 1 (sCR1). It's a molecule featured with both decay accelerator and cofactor activity, additionally showing a potential to inhibit the classical and alternative pathways.
sCR1 exhibited inspiring results in treating I/R injury and several other diseases in experimental animal models. These promising results facilitated the therapeutic drug, TP10, which is widely used after coronary artery bypass graft surgery. A large placebo-controlled phase 2 trial with 564 high-risk patients undergoing cardiac surgery verified the efficacy of TP10 complement. The complement activation was inhibited for up to 3 days by a single intravenous bolus of TP10 immediately before surgery.
The soluble forms of complement regulators have multiple advantages over anti-cytokine antibodies, such as high specificity, high affinity, and less possibility to induce immune responses and attenuate the actions of agents.
Common Soluble Complement Regulators
The increasing recognition of the involvement of complement regulators in health and disease has prompted the development of complement-directed drugs. And a variety of creative therapeutic approaches and products are emerging.
l sCR1/TP10 (Avant Immunotherapeutics)
As aforementioned, the first advance in soluble complement regulators was the expression of sCR1. It has been the most extensively developed regulator of complement activation for a lot of experimental animal disease models, including injury, arthritis, glomerulonephritis, myasthenia gravis, allergic encephalomyelitis, acute myocardial infarction, lung transplantation, and post-cardiopulmonary bypass syndrome.
l CAB-2/MLN-2222 (Millenium Pharmaceuticals)
Soluble forms of MCP, DAF, and CD59 have also been recognized as therapeutics with the development of different approaches for the clinical substitution and inhibition/modulation of complements. Though DAF and MCP each only offer a single regulatory activity, a recombinant chimera of their extracellular parts has been developed with the result of the sDAF-sMCP hybrid, which was initially named "complement activity blocker 2" (CAB-2) and later clinical trials renamed it as MLN-2222.
Recent research indicates that recombinant CD59 may be a promising therapy for paroxysmal nocturnal hemoglobinuria (PNH) as it's related to the decreased expression of membrane-anchored proteins, including CD59 and DAF, on erythrocytes.
Other related regulators include soluble complement inhibitors C4-binding protein (C4BP), factor H, and factor I complement.
C4BP and factor I are responsible for the regulation of C4b, which shows promising effects on the treatment of diseases associated with abnormal or loss of complement control. Factor H performs a deactivator in the complement system. Moreover, C4BP proves to inhibit the classical pathway while factor H inhibits the alternate pathway, which may suppress self cell damages and inflammation.
In brief, complement activation takes an essential part of the mechanism of pathogenesis of human diseases, and soluble complement regulators are encouraging therapeutic targets to suppress or prevent complement-mediated diseases. However, researchers need more experiments based on optimized and validated protocols to develop more effective and safer anti-complement therapeutics, in which the assistance from soluble complement regulator development services will make success with half the effort.