Progress and Trends in Complement Therapeutics

Abstract

The past few years have proven to be a highly successful and exciting period for the field of complement-directed drug discovery and development. Driven by promising experiences with the first marketed complement drugs, increased knowledge about the involvement of complement in health and disease, and improvements in structural and analytical techniques as well as animal models of disease, the field has seen a surge in creative approaches to therapeutically intervene at various stages of the cascade. An impressive panel of compounds that show promise in clinical trials is meanwhile being lined up in the pipelines of both small biotechnology and big pharmaceutical companies. Yet with this new focus on complement-targeted therapeutics, important questions concerning target selection, point and length of intervention, safety, and drug delivery emerge. In view of the diversity of the clinical disorders involving abnormal complement activity or regulation, which include both acute and chronic diseases and affect a wide range of organs, diverse yet specifically tailored therapeutic approaches may be needed to shift complement back into balance. This chapter highlights the key changes in the field that shape our current perception of complement-targeted drugs and provides a brief overview of recent strategies and emerging trends. Selected examples of complement-related diseases and inhibitor classes are highlighted to illustrate the diversity and creativity in field.

Fig. 1.1

Simplified scheme of the complement cascade and major points of therapeutic intervention. Pattern recognition molecules are colored in purple, proteases in green, complement components in blue, regulators in cyan, and receptors in dark red. Red symbols mark major therapeutic classes (small molecules, proteins, and antibodies; see legend) and are depicted next to their target protein. Abbreviations used: C1–C9 complement components 1–9, C1–INH C1 esterase inhibitor, C3aR C3a receptor, C5aR C5a receptor, Conv convertase, CR complement receptor, CRIg complement receptor of the immunoglobulin family, FB factor B, Fcn ficolins, FD factor D, FI factor I, FP properdin, MASPs MBL-associated serine proteases, MBL mannose-binding lectin, RCA regulators of complement activation, TCC terminal complement complex

Fig. 1.2

Diseases and clinical disorders/complications with demonstrated or suspected involvement of complement. Abbreviations used: aHUS atypical hemolytic uremic syndrome, AMD age-related macular degeneration, I/R ischemia/reperfusion, PNH paroxysmal nocturnal hemoglobinuria, SIRS systemic inflammatory response syndrome, SLE systemic lupus erythematosus

Fig. 1.3

Points of therapeutic intervention in the complement cascade and their theoretical effect on activation and effector mechanisms. The cascade organization in all panels corresponds to the one depicted in Fig. 1.1. Green coloring symbolizes unaffected functionality, whereas orange and red tones reflect partial or complete impairment, respectively

Fig. 1.4

Examples of complement-related disorders with different potential requirements concerning drug administration

Fig. 1.5

Modular concept of complement regulators and receptors composed of CCP domains and their use for designing therapeutic complement inhibitors. Colored circles depict individual CCP domains, with regulatory and targeting entities marked in red and pale magenta, respectively. *CAB-2 is not currently listed in the pipeline of Millennium; **Even though Mirococept is not currently listed in the pipelines of pharmaceutical companies, it has recently been evaluated for transplant protection

Fig. 1.6

Approaches to target complement inhibitors to various surfaces either in circulation or after ex vivo coating/perfusion. Regulatory/inhibitory and recognition domains are depicted in dark red and pale pink, respectively. Antibody fragments are shown in purple, sialyl Lewis χ moieties are represented as orange stars, and inhibitory or recruiting peptides in bright red