C3bBb

(C3 convertase)

C3b

C5

C3bBbC3b (C5 convertase)

MAC

Figure 53.1  The alternative complement pathway (simplified to aid in conceptualization).

The principal components of the alternative complement pathway to the stage of C5 convertase production are shown in detail. Initially, C3 is converted spontaneously to C3a and C3b, making C3b available for binding to cell surfaces. On binding to an activator (pathogen) surface, C3b is converted to C3 convertase (C3bBb) through the several steps shown here, of which C3bBa is a byproduct, which in turn upregulates the conversion of C3 to C3b. On binding to an autologous cell surface, C3b is inactivated (iC3b) and the amplification loop is not entered. Complement factor H acts as one of the primary regulators of this pathway by inhibiting the binding of complement factor B to C3b and also by degrading C3b. Reprinted from DeWan A, Bracken MB, Hoh J. Two genetic pathways for age-related macular degeneration. Curr Opin Genet Dev 2007;17,228–233, with permission.

hydrolysis of complement component C3 on the surface of a cell membrane. Once the cleavage product C3b has covalently bonded to a cell it binds factor B, which is then cleaved by factor D. This results in formation of the alternative pathway C3 convertase, C3bBb, which in turn leads to signal amplification by further C3 cleavage, and formation of C5 convertase, and consequently C5 cleavage and formation of the membrane attack complex. Host cells are protected from alternative pathway activation by the presence of complement receptor 1, factor H, the decay-accelerating factor, and the plasma protease, factor I (Figure 53.1).

Genetic polymorphism associations and analysis of the composition of drusen suggest that dysregulation of the complement cascade plays a key role in the development of AMD. In particular, the presence of the complement factor H 402H risk allele appears to be one of the most significant risk factors for the development of soft drusen in some populations.37 Because there is evidence that polymorphisms in many components of the complement cascade are associated with AMD, proposed therapeutic strategies attempt either to block activation of the alternative pathway by inactivating C3, or to inhibit the cascade downstream by binding C5.

POT-4 (Potentia Pharmaceuticals) is a cyclic peptide that binds and inactivates complement component 3. A dose-escalating phase I safety

and tolerability trial of intravitreal POT-4 injections in patients with subfoveal CNV is being conducted.

ARC1905 (Ophthotech) is a pegylated RNA aptamer that inhibits complement component 5. This molecule is also undergoing a doseescalating phase I trial of multiple intravitreal injections in eyes with subfoveal CNV. All patients will be treated with ARC1905. Patients will also be treated with either a single induction dose of ranibizumab or multiple doses of ranibizumab.

Although safety studies are being performed in eyes with neovascular AMD, it is hoped that complement cascade inhibitors may slow the progression of nonneovascular AMD.

DIABETIC MACULAR EDEMA

INHIBITION OF INFLAMMATION

It is hypothesized that inflammatory processes are involved in the pathogenesis of DME, and intravitreal triamcinolone has been demonstrated to be efficacious in improving visual acuity and reducing macular thickness of eyes affected by DME.38 The role of intraocular steroids in DME needs further investigation, as a recent 3-year study has indicated that laser photocoagulation may have better safety and efficacy for DME compared to intravitreal triamcinolone.39 Lymphocyte function-associated antigen-1 is composed of CD11a and CD18. It mediates leukocyte adhesion by binding intercellular adhesion molecules 1–3 and also functions in lymphocyte co-stimulatory signaling.40

The hypothesis that blockade of CD11a by the monoclonal antibody efalizumab may be beneficial in the treatment of DME is being examined in the Combined Approach to Treatment Using Ranibizumab and Efalizumab for Diabetic Macular Edema (CAPTURE DME) study. In this phase I study, the primary endpoint is the evaluation of adverse events. The secondary endpoints are visual acuity and anatomical measures by OCT and fluorescein angiography at 6 and 12 months. In the study, a three-way comparison of efficacy between efalizumab, ranibizumab, and combination therapy of ranibizumab and efalizumab will be performed.

SUMMARY AND KEY POINTS

As the field of pharmacotherapeutics continues to expand for retinal and ocular inflammatory diseases, Retinal Pharmacotherapy has been prepared to provide comprehensive ophthalmologists and retina specialists the basic understanding of relevant ophthalmic drugs and their characteristics. This chapter has given the reader a glimpse of selected future agents in clinical testing, and is not meant to be all-inclusive. It is expected that by the time the first edition of Retinal Pharmacotherapy is printed, preparation of the second edition will have begun in order to accommodate the additional therapeutic agents. In addition, there are several significant areas of therapeutic need that are not met by the therapies described in this book. Such areas include repair of areas of RPE loss, repair of atrophied choriocapillaris, elimination of the fibrotic component of CNV, protection against loss of retinal tissue in diabetic maculopathy and both neovascular and nonneovascular AMD, and protection against macular capillary loss in diabetic retinopathy. Hopefully, with the continuing advancements of basic and clinical research, pharmacotherapy for these and other areas will be covered in future editions of Retinal Pharmacotherapy.

ACKNOWLEDGMENT

The Cole Eye Institute receives research grant support on behalf of Dr. Kaiser from Allergan, Alcon, Genentech, Quark, Pfizer, Novartis, and QLT. Dr. Kaiser has received honoraria that have been disclosed to the

Words Last The • 6 section

horizon the on agents perspectives: • 53Futurechapter

conflict of interest committee of the Cleveland Clinic from Alcon, Genentech, Novartis, Allergan, and QLT.

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