A humanized antibody that binds to the interleukin 2 receptor.

Abstract

The anti-Tac monoclonal antibody is known to bind to the p55 chain ofthe human interleukin 2 receptor and to inhibit proliferation of T cells by blocking interleukin 2 binding. However, use of anti-Tac as an immunosuppressant drug would be impaired by the human immune response against this murine antibody. We have therefore constructed a "humanized" antibody by combining the complementaritydetermining regions (CDRs) of the anti-Tac antibody with human framework and constant regions. The human framework regions were chosen to maximize homology with the anti-Tac antibody sequence. In addition, a computer model of murine anti-Tac was used to identify several amino acids which, while outside the CDRs, are likely to interact with the CDRs or antigen. These mouse amino acids were also retained in the humanized antibody. The humanized anti-Tac antibody has an affinity for p55 of 3 x 109 M-1, about

Effect of Anti‐IL‐2Rα Antibody on IL‐2‐induced Jak/STAT Signaling

“…Daclizumab (humanized anti-Tac, HAT) is a humanized monoclonal IgG 1 antibody that incorporates the complementaritydetermining regions of a murine monoclonal antibody raised against the human IL-2Ra chain (3,4). The humanized antibody, directed towards an epitope on the a chain of the IL-2R (epitope A), was derived from a murine monoclonal antibody (anti-Tac) that had previously demonstrated effective rejection prophylaxis in clinical trials (5).…”

“…Advances in molecular engineering led to development of daclizumab, allowing it to be administered for long periods of time without eliciting a strong host immune response to the infused antibody. (3,6). Clonal expansion of T cells occurs through IL-2R-mediated signaling pathways that are evoked by IL-2/IL-2R ligation.…”

Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma

“…We joined with Cary Queen to generate a humanized version of the anti-Tac monoclonal antibody (daclizumab) that is reactive with the human IL-2R alpha subunit (Queen et al, 1989;Junghans et al, 1990). In this effort, the human IgG1 framework sequence from the Eu-myeloma antibody was chosen to be as homologous as possible to the original mouse antibody to reduce any deformation of the mouse complementarity determining regions (CDRs).…”

“…This latter action proved to be critical in generating a high-affinity humanized anti-Tac (daclizumab). The parent murine anti-Tac molecule had an affinity of 9 Â 10 À9 M to its target IL-2R alpha, whereas the hyperchimeric humanized version had an affinity of 3 Â 10 À9 M -still very high (Queen et al, 1989). The original humanized anti-Tac monoclonal antibody, daclizumab, and the parent murine version manifested comparable inhibition of the T-cell proliferation in response to the tetanus-toxoid antigen indicating that humanization was not associated with the loss of functional activity.…”

Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody

“…Furthermore, binding to MAT was not displaced by UPC 10, but MAT was displaced both by MAT and by humanized anti-Tac, HAT, which shares only the CDRs and six framework residues with MAT. 29,31 ('cc␣Id' is discussed below.) The persistent HAMA response to MAT in this patient was therefore predominantly anti-idiotypic.…”