Polyclonal antibodies, such as anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG), are prepared by inoculating rabbits or horses with human lymphocytes or thymocytes and collecting their serum following immunisation. The IgG fraction is purified, but contains antibodies not only to lymphocytes, but also to platelets and red cells. ATG and ALG are fully xenogeneic and are therefore recognised by the recipient’s immune system as foreign, resulting in the development of neutralising antibodies. This prevents recurrent use. Despite this limitation, the lack of specificity and the development of a first-dose reaction, the so-called ‘cytokine release syndrome’ that follows cell lysis in up to 80% of patients, ATG is still used to treat steroid-resistant rejection.
Monoclonal antibodies (mAbs) are derived from a single plasma cell clone, and thus have a single specificity. The first mAb used in transplantation was the anti-CD3 antibody Muromonab-CD3 (OKT3). This has the advantage of specificity, targeting only T cells, but patients may still develop a cytokine release syndrome. Furthermore, OKT3 is a fully xenogeneic protein and thus antibodies are raised against it, limiting efficacy. Newer mAb are comprised of a murine variable region and a human Fc portion (chimeric antibodies, e.g. basiliximab) or are more fully humanised with only a xenogenic complementarity-determining region (CDR), e.g. alemtuzumab, where the CDRs are of rat origin. The nomenclature of mAbs allows the identification of the source of antibody by the letters preceding the mAb stem. For chimeric antibodies, the source substem ‘-xi-’ are used, whereas for humanised antibodies, the substem ‘-zu-’ is used. All mAb now end with the stem-mab.
An alternative to humanised mAbs is the construction of fusion proteins (FPs), in which the Fc part of human IgG1 is fused with a human soluble receptor or ligand of a target molecule. FPs are novel molecules but are composed of fully human subunits, limiting the development of neutralising antibodies. The addition of the Fc portion of IgG1 prolongs the half-life of the soluble receptor or ligand. In transplantation, belatacept, a modified CTLA-4 fusion protein, has been used as a maintenance agent in place of calcineurin inhibitors.