CR2-Mediated Targeting of Complement Inhibitors: Bench-to-Bedside Using a Novel Strategy for Site-Specific Complement Modulation

Abstract

Recent approval of the first human complement pathway-directed therapeutics, along with high-profile genetic association studies, has catalyzed renewed biopharmaceutical interest in developing drugs that modulate the complement system. Substantial challenges remain, however, that must be overcome before widespread application of complement inhibitors in inflammatory and autoimmune diseases becomes possible. Among these challenges are the following: (1) defining the complement pathways and effector mechanisms that cause tissue injury in humans and determining whether the relative importance of each varies by disease, (2) blocking or modulating, using traditional small molecule or biologic approaches, the function of complement proteins whose circulating levels are very high and whose turnover rates are relatively rapid, especially in the setting of acute and chronic autoimmune diseases, and (3) avoiding infectious complications or impairment of other important physiological functions of complement when using systemically active complement-blocking agents. This chapter will review data that address these challenges to therapeutic development, with a focus on the development of a novel strategy of blocking specific complement pathways by targeting inhibitors using a recombinant portion of the human complement receptor type 2 (CR2/CD21) which specifically targets to sites of local complement C3 activation where C3 fragments are covalently fixed. Recently, the first of these CR2-targeted proteins has entered human phase I studies in the human disease paroxysmal nocturnal hemoglobinuria. The results of murine translational studies using CR2-targeted inhibitors strongly suggest that a guiding principle going forward in complement therapeutic development may well be to focus on developing strategies to modulate the pathway as precisely as possible by physically localizing therapeutic inhibitory effects.

Structural insight on the recognition of surface-bound opsonins by the integrin I domain of complement receptor 3

“…Our structure of the C3d:I domain complex provides an important contribution to the development of more selective complement inhibitors by identifying the surface areas on the CR3 I domain and on the C3d moiety of importance for their mutual interaction. Owing to the proximity of the C3d-CR2 interaction it may also contribute to improve the CR2-based targeting strategies under development for site-specific delivery of complement inhibitors (49 (20). (D) Silver-stained gel after denaturing SDS/PAGE analysis of fractions from the CR3 I domain affinity column.…”

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

“…TT30 combines the regulatory CCP1-5 of FH with the N-terminal four domains of CR2 that bind to iC3b, C3dg and C3d. Thereby, TT30 inhibits AP activity (by accelerating the decay of convertases and acting as a cofactor for the factor I-mediated degradation of C3b to prevent further C3/C5 convertase formation) on sites of ongoing complement activation that typically accumulate these downstream opsonins (41, 42). TT30 and its rodent homologs have shown promising results for AP-specific complement inhibition in disease models ranging from AMD to PNH (41, 43, 44), and TT30 is now being evaluated in phase I trials for PNH (NCT01335165).…”

“…Thereby, TT30 inhibits AP activity (by accelerating the decay of convertases and acting as a cofactor for the factor I-mediated degradation of C3b to prevent further C3/C5 convertase formation) on sites of ongoing complement activation that typically accumulate these downstream opsonins (41, 42). TT30 and its rodent homologs have shown promising results for AP-specific complement inhibition in disease models ranging from AMD to PNH (41, 43, 44), and TT30 is now being evaluated in phase I trials for PNH (NCT01335165). This targeting approach has been extended to combine the N-terminal regions of CR1 and CR2 (TT32), thereby producing an inhibitor with activities for both CP/LP and AP (by acting on C4b and C3b, respectively) that has been tested in an arthritis model (45).…”

The Role of Complement in Membranous Nephropathy

“…Some of these will be broadly active, such as eculizumab, and target general processes such as the cleavage of C5. Others are being developed as chimeric molecules that will be targeted only to areas in which there is active complement activation 99 . Although the definitive therapy in MN will be to administer immunosuppressive therapy to bring about the disappearance of circulating autoantibodies (or to treat the underlying systemic disease or exposure in secondary forms), there will be a window period in which circulating antibodies, antigen, or both will continue to lead to ongoing formation of immune deposits and sublethal injury of podocytes via complement activation.…”