T-Cell Costimulation
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《新英格兰医药杂志》
To the Editor: In their Perspective article, Sharpe and Abbas (Sept. 7 issue)1 discuss possible explanations for the adverse events associated with a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412, as reported by Suntharalingam et al.2 Sharpe and Abbas suggest that a difference in affinity for CD28 between species may be important.1 However, an alternative explanation relates to differences in Fc-receptor binding between species, which is dependent on the isotype of the monoclonal antibody.3 It is for this reason that anti-CD3 monoclonal antibodies (signal 1) have been engineered to reduce Fc-receptor binding. This process results in less cross-linking of CD3 on the T-cell surface (through Fc-receptor binding) and consequently in little release of cytokines.4 TGN1412 is a human IgG4 monoclonal antibody. Previous studies in nonhuman primates have demonstrated that this isotype is ineffective in engaging Fc receptors.5 Although TGN1412 was used at 1/500 of the dose that was used safely in nonhuman primates, increased avidity of the IgG4 Fc region for human Fc receptors may have caused sufficient cross-linking of CD28 to elicit a cytokine storm. Such a hypothesis could be tested experimentally.
Matt P. Wise, D.Phil.
University Hospital of Wales
Cardiff CF14 4XW, United Kingdom
mattwise@doctors.org.uk
Awen Gallimore, D.Phil.
Andrew Godkin, M.D.
Cardiff University
Cardiff CF14 4XN, United Kingdom
References
Sharpe AH, Abbas AK. T-cell costimulation -- biology, therapeutic potential, and challenges. N Engl J Med 2006;355:973-975.
Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006;355:1018-1028.
Hale G, Clark M, Waldmann H. Therapeutic potential of rat monoclonal antibodies: isotype specificity of antibody-dependent cell-mediated cytotoxicity with human lymphocytes. J Immunol 1985;134:3056-3061.
Friend PJ, Hale G, Chatenoud L, et al. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 1999;68:1632-1637.
Mourad GJ, Preffer FI, Wee SL, et al. Humanized IgG1 and IgG4 anti-CD4 monoclonal antibodies: effects on lymphocytes, blood, lymph nodes, and renal allografts in cynomolgus monkeys. Transplantation 1998;65:632-641.
To the Editor: Sharpe and Abbas suggest that possible differences in the activation requirements of naive T cells and memory T cells could explain the lack of a biologic signal in animals. Another explanation, they say, is a possible difference in the affinity of the anti-CD28 monoclonal antibody for human and primate CD28 molecules. The accompanying article by Suntharalingam et al. does not discuss possible mechanisms of cytokine-storm induction but does note that similar reactions have been observed in previous trials of some antilymphocyte antibodies. A third possibility — distinct from the specificity of the antibody but more consistent with data from previous antibody trials, which also showed cytokine release syndromes — is that cytokine release is induced by the binding of Fc to Fc receptors. Apart from the cytokine release syndromes, such binding would also induce the superactivation of T cells and would explain the immunopathology that is seen.1
Camilo A.L.S. Colaco, Ph.D.
ImmunoBiology
Cambridge CB2 4AT, United Kingdom
camilo.colaco@immunbiology.co.uk
References
Colaco C. What went horribly wrong in a London clinical trial. Scientist 2006;20:14-14.
The authors reply: Wise et al. and Colaco note an additional possible mechanism for the cytokine release syndrome, related to Fc-receptor binding. Species differ greatly with respect to the number of Fc-receptor genes and specific cell-type expression patterns. We really do not understand the differences between nonhuman primates and humans with respect to the diversity of Fc receptors, and we lack information to make cross-species comparisons of the binding of human IgG subclasses to Fc receptors in nonhuman primates.1 There is a need for better models to address these issues. It should be noted that differences in both the antibody subclass and the glycosylation status of the antibody influence the profile of Fc-receptor binding. In addition, human IgG4 has a low level of binding to Fc receptors but is not a nonbinder. Clearly, it is important to consider the nature of the Fc portion of antibodies as they are developed for clinical use as therapeutic agents.2
Arlene Sharpe, M.D., Ph.D.
Harvard Medical School
Boston, MA 02115
Abul Abbas, M.D.
University of California, San Francisco
San Francisco, CA 94143
References
Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin resulting fron Fc sialylation. Science 2006;313:670-673.
Nimmerjahn F, Ravetch JV. Fc gamma receptors: old friends and new family members. Immunity 2006;24:19-28.
Matt P. Wise, D.Phil.
University Hospital of Wales
Cardiff CF14 4XW, United Kingdom
mattwise@doctors.org.uk
Awen Gallimore, D.Phil.
Andrew Godkin, M.D.
Cardiff University
Cardiff CF14 4XN, United Kingdom
References
Sharpe AH, Abbas AK. T-cell costimulation -- biology, therapeutic potential, and challenges. N Engl J Med 2006;355:973-975.
Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006;355:1018-1028.
Hale G, Clark M, Waldmann H. Therapeutic potential of rat monoclonal antibodies: isotype specificity of antibody-dependent cell-mediated cytotoxicity with human lymphocytes. J Immunol 1985;134:3056-3061.
Friend PJ, Hale G, Chatenoud L, et al. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 1999;68:1632-1637.
Mourad GJ, Preffer FI, Wee SL, et al. Humanized IgG1 and IgG4 anti-CD4 monoclonal antibodies: effects on lymphocytes, blood, lymph nodes, and renal allografts in cynomolgus monkeys. Transplantation 1998;65:632-641.
To the Editor: Sharpe and Abbas suggest that possible differences in the activation requirements of naive T cells and memory T cells could explain the lack of a biologic signal in animals. Another explanation, they say, is a possible difference in the affinity of the anti-CD28 monoclonal antibody for human and primate CD28 molecules. The accompanying article by Suntharalingam et al. does not discuss possible mechanisms of cytokine-storm induction but does note that similar reactions have been observed in previous trials of some antilymphocyte antibodies. A third possibility — distinct from the specificity of the antibody but more consistent with data from previous antibody trials, which also showed cytokine release syndromes — is that cytokine release is induced by the binding of Fc to Fc receptors. Apart from the cytokine release syndromes, such binding would also induce the superactivation of T cells and would explain the immunopathology that is seen.1
Camilo A.L.S. Colaco, Ph.D.
ImmunoBiology
Cambridge CB2 4AT, United Kingdom
camilo.colaco@immunbiology.co.uk
References
Colaco C. What went horribly wrong in a London clinical trial. Scientist 2006;20:14-14.
The authors reply: Wise et al. and Colaco note an additional possible mechanism for the cytokine release syndrome, related to Fc-receptor binding. Species differ greatly with respect to the number of Fc-receptor genes and specific cell-type expression patterns. We really do not understand the differences between nonhuman primates and humans with respect to the diversity of Fc receptors, and we lack information to make cross-species comparisons of the binding of human IgG subclasses to Fc receptors in nonhuman primates.1 There is a need for better models to address these issues. It should be noted that differences in both the antibody subclass and the glycosylation status of the antibody influence the profile of Fc-receptor binding. In addition, human IgG4 has a low level of binding to Fc receptors but is not a nonbinder. Clearly, it is important to consider the nature of the Fc portion of antibodies as they are developed for clinical use as therapeutic agents.2
Arlene Sharpe, M.D., Ph.D.
Harvard Medical School
Boston, MA 02115
Abul Abbas, M.D.
University of California, San Francisco
San Francisco, CA 94143
References
Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin resulting fron Fc sialylation. Science 2006;313:670-673.
Nimmerjahn F, Ravetch JV. Fc gamma receptors: old friends and new family members. Immunity 2006;24:19-28.