Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol-anchored glycoprotein which is an exceptionally good target for complement lysis

Abstract

CAMPATH-1 antibodies recognize a unique molecule on human lymphocytes and are unusually efficient at causing cell lysis with homologous complement. They have been successfully used for lymphocyte depletion in vivo in a variety of diseases. We find that the antigen is a very small glycosylphosphatidylinositol (GPI)-anchored glycoprotein with a mature peptide comprising only 12 amino acids. It can be separated into two distinct antigenic fractions which differ in their susceptibility to phosphatidylinositol-specific phospholipase C. There is one N-linked glycosylation site, but no evidence for O-glycosylation despite the presence of several serine and threonine residues. The antibodies were found to bind, albeit with a generally reduced affinity, to a proteolytic fragment containing the C-terminal tripeptide and the GPI anchor. We postulate that one of the reasons why the CAMPATH-1 antibodies are so good for cell lysis is because they bind to an epitope which is likely to be very close to the lipid bilayer.

Free circulating soluble CD52 as a tumor marker in chronic lymphocytic leukemia and its implication in therapy with anti‐CD52 antibodies

“…[1][2][3] The C-terminus is anchored on the cell membrane by a glycosylphosphatidylinositol (GPI) lipid. 2,4 CD52 is expressed on the surface of T and B lymphocytes, monocytes/macrophages, eosinophils, and on some early hematopoietic cells.…”

“…11 Later studies showed that CAMPATH-1 antibodies recognize CD52. 1,10,12 The immunoglobulin G1 (IgG1) form of CAMPATH-1 was humanized and this agent, alemtuzumab (CAMPATH-1H), was recently approved for the treatment of patients with refractory chronic lymphocytic leukemia (CLL). 13 The CAMPATH-1 family of antibodies is also being used in vitro for lymphocyte depletion in recipients of allogeneic bone marrow grafts, and is being investigated as an immunomodulatory therapy in a variety of diseases.…”

Alemtuzumab Therapy for Multiple Sclerosis

“…Alemtuzumab binds to CD52, a 12-amino acid cell surface protein of unknown function [10][11][12] that is expressed at high levels on T cells and B cells and at lower levels on monocytes, macrophages, and eosinophils with little found on Natural Killer cells, neutrophils, and hematological stem cells. Cells of the innate immune system are unaffected.…”

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

“…Importantly, however, its expression on CD34 + HSCs is low [27]. Binding of alemtuzumab to CD52 leads to cytotoxicity through different mechanisms, including antibody-mediated cytolysis [28], complement-induced membrane attack complex [29], and apoptosis [30,31]. The cytolytic effects of alemtuzumab lead to prolonged lymphopenia and a complete reconstitution of T-lymphocyte populations may take as long as 5 years [32].…”