Biological Agents
Polyclonal antibodies
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
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.
Fusion proteins
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.
