title: Characterisation of a Novel Anti-CD52 Antibody with Improved Efficacy and Reduced Immunogenicity.
abstract: Anti-CD52 therapy has been shown to be effective in the treatment of a number of B cell malignancies, hematopoietic disorders and autoimmune diseases (including rheumatoid arthritis and multiple sclerosis); however the current standard of treatment, the humanized monoclonal antibody alemtuzumab, is associated with the development of anti-drug antibodies in a high proportion of patients. In order to address this problem, we have identified a novel murine anti-CD52 antibody which has been humanized using a process that avoids the inclusion within the variable domains of non-human germline MHC class II binding peptides and known CD4+ T cell epitopes, thus reducing its potential for immunogenicity in the clinic. The resultant humanized antibody, ANT1034, was shown to have superior binding to CD52 expressing cells than alemtuzumab and was more effective at directing both antibody dependent and complement dependent cell cytotoxicity. Furthermore, when in the presence of a cross-linking antibody, ANT1034 was more effective at directly inducing apoptosis than alemtuzumab. ANT1034 also showed superior activity in a SCID mouse/human CD52 tumour xenograft model where a single 1 mg/Kg dose of ANT1034 led to increased mouse survival compared to a 10 mg/Kg dose of alemtuzumab. Finally, ANT1034 was compared to alemtuzumab in in vitro T cell assays in order to evaluate its potential to stimulate proliferation of T cells in peripheral blood mononuclear cells derived from a panel of human donors: whereas alemtuzumab stimulated proliferation in a high proportion of the donor cohort, ANT1034 did not stimulate proliferation in any of the donors. Therefore we have developed a candidate therapeutic humanized antibody, ANT1034, that may have the potential to be more efficacious and less immunogenic than the current standard anti-CD52 therapy.
authors.affiliation: Antitope Limited, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: Robert G E
authors.initials: RG
authors.lastname: Holgate
authors.affiliation: Antitope Limited, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Weldon
authors.affiliation: Antitope Limited, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Jones
authors.affiliation: Antitope Limited, Babraham Research Campus, Cambridge, United Kingdom.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Baker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D000074301:CD52 Antigen; D045744:Cell Line, Tumor; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; D011993:Recombinant Fusion Proteins