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CD52 antigen as a target for immunotherapy
CD52 Antigen as a Target for Immunotherapy Geoff Hale
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he antigenic epitope CD52 is expressed on the surface membranes of peripheral blood lymphocytes, monocytes, and macrophages, as well as the epithelial lining of the male reproductive system. The structural features of the CD52 antigen, specifically its small size, lateral mobility, and closeness to the cell membrane, as well as the sheer abundance of the antigen (CD52 is expressed on ⬃5% of the lymphocyte surface), make it an ideal target for antibody-mediated killing1 (Fig 1). Alemtuzumab (CAMPATH威 1H; ILEX™ Oncology, Inc [ILEX], San Antonio, TX), a humanized monoclonal antibody against the CD52 epitope, has a relatively low affinity and requires a concentration of approximately 50 g/mL to achieve maximum binding2 (Fig 2). Nevertheless, it is an extremely potent agent for depletion of lymphocytes in vivo, and a short course of treatment with as little as 40 mg (total) gives rapid and long-lasting depletion of lymphocytes, particularly CD4 cells, in transplant patients.3,4 The potent activity of alemtuzumab appears to be primarily initiated through cell-mediated killing (antibody-dependent cell-mediated cytotoxicity), which is maximal at concentrations as low as 10 ng/mL, whereas optimum activation of complement-mediated lysis requires concentrations of 10 g/mL5 (Fig 3). In patients with chronic lymphocytic leukemia, the indication for which alemtuzumab is approved, both the route of administration and the tumor burden influence the time necessary to achieve peak serum levels. The time to reach peak serum antibody levels is shorter with intravenous administration than with subcutaneous administration, and the blood levels reached after intravenous administration are higher in patients who have a good clinical response. In contrast, serum levels among bone marrow transplant recipients were more consistent
From the Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom. Address reprint requests to Geoff Hale, PhD, Therapeutic Antibody Centre, Old Road, Headington, Oxford OX3 7JT, United Kingdom. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/S0955-470X(03)00073-9
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Figure 1. Structure of the CD52 antigen showing the closeness of the Campath epitope to the lipid anchor. (Modified and reprinted with permission from Hale G. The CD52 antigen and development of the CAMPATH antibodies. Cytotherapy 2001; 3:137. Published by Taylor & Francis.)
among patients, presumably because they did not have a substantial burden of CD52⫹ tumor cells.4 Pharmacokinetic analysis of serum from bone marrow transplant recipients shows that the half-life of alemtuzumab is in the range of 1 to 3 weeks. Therapeutic antibodies have long been used to mediate immunosuppression and prevent acute rejection in transplant recipients. An issue with antibody therapy, however, is the development of antiantibodies that can limit efficacy. Antithymocyte globulin is currently the most commonly used T-cell– depleting agent for induction therapy in kidney transplant recipients. Although antithymocyte globulin has been associated with high graft survival rates (⬃98%) and low infection rates (⬃10%), the potential for development of xenogeneic antibodies is high (⬃78%). Muromonab anti-CD3 (OKT3) is less immunogenic; however, human antimouse antibody development is possible because of its murine origin. Because alemtuzumab is a humanized
Transplantation Reviews, Vol 17, No 4 (October), 2003: pp S8-S9
CD52 Antigen and Immunotherapy
monoclonal antibody, the potential for an immunogenic response is decreased significantly. Anti-idiotypic responses have not been observed among kidney transplant recipients treated with a single course of alemtuzumab.6 Cytokine release syndrome is common with antilymphocyte antibody therapy. High-dose steroid pretreatment is mandatory for patients treated with muromonab anti-CD3, who may experience major infusion-related adverse experiences. Although treatment with alemtuzumab has been associated with the “first-dose effects” of pyrexia, urticarial rash, nausea, vomiting, headache, and rigors as a result of cytokine release syndrome, these effects are usually low grade in nature and well limited with steroid pretreatment. In summary, the CD52 is an extraordinary target for lymphocyte-depletion therapy, as indicated by the potent and immediate response to alemtuzumab, as well as the overall good safety profile evidenced by no
S9
Figure 3. Killing of human lymphocytes by Campath; comparison of cell-mediated (ADCC, antibody-dependent cell-mediated cytotoxicity) and complement-mediated cytotoxicity. Cell lysis was measured by release of chromium 51. (Adapted and reprinted with permission from Riechmann L, Clark M, Waldmann H, et al. Reshaping human antibodies for therapy. Nature 1988, 332:323.)
clinical evidence of anti-idiotypic responses and manageable cytokine effects. Additionally, alemtuzumab has a simple regimen of single, low-dose intravenous infusions, thus reducing the likelihood of long-term safety issues and patient compliance.
References
Figure 2. Binding of Campath to the human T-cell line HUT-78 measured by flow cytometry. (Reprinted from Journal of Immunological Methods, Vol 260, Rebello P, Hale G, Pharmacokinetics of Campath-1H: assay development and validation, pages 285-302, copyright 2002, with permission from Elsevier.)
1. Hale G: The CD52 antigen and development of the Campath antibodies. Cytotherapy 2001, 3:137 2. Rebello P, Hale G: Pharmacokinetics of Campath-1H: Assay development and validation. J Immunol Methods 2002, 260:285 3. Calne R, Moffatt SD, Friend PJ, et al: Campath-1H allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 1999, 68:1613 4. Rebello P, Cwynarski K, Varughese M, et al: Pharmacokinetics of CAMPATH-1H in BMT patients. Cytotherapy 2001, 3:261 5. Riechmann L, Clark M, Waldmann H, et al: Reshaping human antibodies for therapy. Nature 1988, 332:323 6. Rebello PR, Hale G, Friend PJ, et al: Anti-globulin responses to rat and humanised Campath-1H monoclonal antibody used to treat transplant rejection. Transplantation 1999, 68:1417
T
he antigenic epitope CD52 is expressed on the surface membranes of peripheral blood lymphocytes, monocytes, and macrophages, as well as the epithelial lining of the male reproductive system. The structural features of the CD52 antigen, specifically its small size, lateral mobility, and closeness to the cell membrane, as well as the sheer abundance of the antigen (CD52 is expressed on ⬃5% of the lymphocyte surface), make it an ideal target for antibody-mediated killing1 (Fig 1). Alemtuzumab (CAMPATH威 1H; ILEX™ Oncology, Inc [ILEX], San Antonio, TX), a humanized monoclonal antibody against the CD52 epitope, has a relatively low affinity and requires a concentration of approximately 50 g/mL to achieve maximum binding2 (Fig 2). Nevertheless, it is an extremely potent agent for depletion of lymphocytes in vivo, and a short course of treatment with as little as 40 mg (total) gives rapid and long-lasting depletion of lymphocytes, particularly CD4 cells, in transplant patients.3,4 The potent activity of alemtuzumab appears to be primarily initiated through cell-mediated killing (antibody-dependent cell-mediated cytotoxicity), which is maximal at concentrations as low as 10 ng/mL, whereas optimum activation of complement-mediated lysis requires concentrations of 10 g/mL5 (Fig 3). In patients with chronic lymphocytic leukemia, the indication for which alemtuzumab is approved, both the route of administration and the tumor burden influence the time necessary to achieve peak serum levels. The time to reach peak serum antibody levels is shorter with intravenous administration than with subcutaneous administration, and the blood levels reached after intravenous administration are higher in patients who have a good clinical response. In contrast, serum levels among bone marrow transplant recipients were more consistent
From the Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom. Address reprint requests to Geoff Hale, PhD, Therapeutic Antibody Centre, Old Road, Headington, Oxford OX3 7JT, United Kingdom. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/S0955-470X(03)00073-9
S8
Figure 1. Structure of the CD52 antigen showing the closeness of the Campath epitope to the lipid anchor. (Modified and reprinted with permission from Hale G. The CD52 antigen and development of the CAMPATH antibodies. Cytotherapy 2001; 3:137. Published by Taylor & Francis.)
among patients, presumably because they did not have a substantial burden of CD52⫹ tumor cells.4 Pharmacokinetic analysis of serum from bone marrow transplant recipients shows that the half-life of alemtuzumab is in the range of 1 to 3 weeks. Therapeutic antibodies have long been used to mediate immunosuppression and prevent acute rejection in transplant recipients. An issue with antibody therapy, however, is the development of antiantibodies that can limit efficacy. Antithymocyte globulin is currently the most commonly used T-cell– depleting agent for induction therapy in kidney transplant recipients. Although antithymocyte globulin has been associated with high graft survival rates (⬃98%) and low infection rates (⬃10%), the potential for development of xenogeneic antibodies is high (⬃78%). Muromonab anti-CD3 (OKT3) is less immunogenic; however, human antimouse antibody development is possible because of its murine origin. Because alemtuzumab is a humanized
Transplantation Reviews, Vol 17, No 4 (October), 2003: pp S8-S9
CD52 Antigen and Immunotherapy
monoclonal antibody, the potential for an immunogenic response is decreased significantly. Anti-idiotypic responses have not been observed among kidney transplant recipients treated with a single course of alemtuzumab.6 Cytokine release syndrome is common with antilymphocyte antibody therapy. High-dose steroid pretreatment is mandatory for patients treated with muromonab anti-CD3, who may experience major infusion-related adverse experiences. Although treatment with alemtuzumab has been associated with the “first-dose effects” of pyrexia, urticarial rash, nausea, vomiting, headache, and rigors as a result of cytokine release syndrome, these effects are usually low grade in nature and well limited with steroid pretreatment. In summary, the CD52 is an extraordinary target for lymphocyte-depletion therapy, as indicated by the potent and immediate response to alemtuzumab, as well as the overall good safety profile evidenced by no
S9
Figure 3. Killing of human lymphocytes by Campath; comparison of cell-mediated (ADCC, antibody-dependent cell-mediated cytotoxicity) and complement-mediated cytotoxicity. Cell lysis was measured by release of chromium 51. (Adapted and reprinted with permission from Riechmann L, Clark M, Waldmann H, et al. Reshaping human antibodies for therapy. Nature 1988, 332:323.)
clinical evidence of anti-idiotypic responses and manageable cytokine effects. Additionally, alemtuzumab has a simple regimen of single, low-dose intravenous infusions, thus reducing the likelihood of long-term safety issues and patient compliance.
References
Figure 2. Binding of Campath to the human T-cell line HUT-78 measured by flow cytometry. (Reprinted from Journal of Immunological Methods, Vol 260, Rebello P, Hale G, Pharmacokinetics of Campath-1H: assay development and validation, pages 285-302, copyright 2002, with permission from Elsevier.)
1. Hale G: The CD52 antigen and development of the Campath antibodies. Cytotherapy 2001, 3:137 2. Rebello P, Hale G: Pharmacokinetics of Campath-1H: Assay development and validation. J Immunol Methods 2002, 260:285 3. Calne R, Moffatt SD, Friend PJ, et al: Campath-1H allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 1999, 68:1613 4. Rebello P, Cwynarski K, Varughese M, et al: Pharmacokinetics of CAMPATH-1H in BMT patients. Cytotherapy 2001, 3:261 5. Riechmann L, Clark M, Waldmann H, et al: Reshaping human antibodies for therapy. Nature 1988, 332:323 6. Rebello PR, Hale G, Friend PJ, et al: Anti-globulin responses to rat and humanised Campath-1H monoclonal antibody used to treat transplant rejection. Transplantation 1999, 68:1417