From functions to mechanisms of the prototypic complement C5 antibody BB5.1

Summary

Antibodies that bind complement components were first identified over 30 years ago. Investigations into their functions in animal models motivated clinical studies that have now generated licensed products and a strong pipeline of future therapeutics. Despite this, the mechanisms of action of one of the first effective C5‐binding antibodies, BB5.1, were not known. Here, we report a new study that reveals these mechanisms, enabling new approaches for designing C5‐binding molecules for therapeutic use.

Proper functioning of the complement system is critical to the health of all vertebrates. The complement proteins that make up the system circulate in the blood. After being triggered by pathogen‐associated patterns or by antigen:antibody complexes, they interact with each other in a cascade. Products of the complement cascade recruit immune cells, coat pathogens enabling them to be phagocytosed, and directly kill target cells. These functions have been widely researched and are not only critical for mediating protection against bacterial pathogens, ¹ but can also contribute to tissue damage when dysregulated, for instance in animal models of systemic lupus erythematosus, ² myasthenia gravis ³ and autoimmune uveoretinitis. ⁴ Therefore, when this system fails, as can occur in people with rare hereditary deficiencies or due to chronic inflammation, the consequences can be extremely serious, leading to persistent infections or autoimmunity. ⁵

A key element of the complement cascade involves the protein C5, which is cleaved by a complex of other complement proteins to generate smaller fragments, called C5a and C5b. Both of these cleaved C5 components have critical downstream functions. C5a is a potent inducer of local inflammatory responses, for instance acting to increase vascular permeability and recruit phagocytes to the activation site. C5b is a key component of the complex multimolecular ‘membrane attack complex’ that is able to puncture the lipid bilayer of a target cell, eventually leading to its death.

Because of the central roles of C5 in the complement cascade, antibodies that bind C5 and inhibit its functions have been the focus of much research. In recent years, for instance, we have reported a study that described new methods for C5 purification, ⁶ and work that identified novel anti‐C5 antibodies with cross‐species specificity. ⁷ This latter paper was highlighted in Immunology in July 2019.

Research into the functions of C5 has led to the development of therapeutic antibodies to treat conditions where complement overactivation causes pathology. The first of these products to be licensed, eculizumab, inhibits C5 cleavage. Although it brings a documented increased risk for meningococcal infection, eculizumab is licensed for use in individuals with paroxysmal nocturnal haemoglobinuria ⁸ and in other rare disorders of complement dysregulation.

The archetypal anti‐C5 antibody was described, in the mouse, in 1987. ⁹ Work using this antibody, which demonstrated the potential utility of inhibiting C5 functions in a range of immune‐mediated conditions, catalysed investigations into applications of anti‐human C5 antibodies, leading to the licensing of eculizumab, with 28 other anticomplement antibodies currently in clinical development. Despite the influence of studies involving the BB5.1 antibody, the binding characteristics and mechanism of action of this important antibody were not known. Here, we highlight a paper that reveals these details, ¹⁰ showing the species specificity, low off‐rate, inhibition of C5a generation and the likely BB5.1:C5‐binding site. These results now enable the development of BB5.1‐derived molecules for novel proof‐of‐concept studies that will broaden the applications of this important class of therapeutic molecules.