To the Editor: In their Perspective article, Sharpe and Abbas(Sept. 7 issue)1 discuss possible explanations for the adverseevents associated with a phase 1 trial of the anti-CD28 monoclonalantibody TGN1412, as reported by Suntharalingam et al.2 Sharpeand Abbas suggest that a difference in affinity for CD28 betweenspecies may be important.1 However, an alternative explanationrelates to differences in Fc-receptor binding between species,which is dependent on the isotype of the monoclonal antibody.3It is for this reason that anti-CD3 monoclonal antibodies (signal1) have been engineered to reduce Fc-receptor binding. Thisprocess results in less cross-linking of CD3 on the T-cell surface(through Fc-receptor binding) and consequently in little releaseof cytokines.4 TGN1412 is a human IgG4 monoclonal antibody.Previous studies in nonhuman primates have demonstrated thatthis isotype is ineffective in engaging Fc receptors.5 AlthoughTGN1412 was used at 1/500 of the dose that was used safely innonhuman primates, increased avidity of the IgG4 Fc region forhuman Fc receptors may have caused sufficient cross-linkingof CD28 to elicit a cytokine storm. Such a hypothesis couldbe tested experimentally.
Matt P. Wise, D.Phil. University Hospital of Wales Cardiff CF14 4XW, United Kingdom mattwise{at}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. [Free Full Text]
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. [Free Full Text]
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. [Abstract]
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. [Web of Science][Medline]
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. [CrossRef][Web of Science][Medline]
To the Editor: Sharpe and Abbas suggest that possible differencesin the activation requirements of naive T cells and memory Tcells could explain the lack of a biologic signal in animals.Another explanation, they say, is a possible difference in theaffinity of the anti-CD28 monoclonal antibody for human andprimate CD28 molecules. The accompanying article by Suntharalingamet al. does not discuss possible mechanisms of cytokine-storminduction but does note that similar reactions have been observedin previous trials of some antilymphocyte antibodies. A thirdpossibility — distinct from the specificity of the antibodybut more consistent with data from previous antibody trials,which also showed cytokine release syndromes — is thatcytokine release is induced by the binding of Fc to Fc receptors.Apart from the cytokine release syndromes, such binding wouldalso induce the superactivation of T cells and would explainthe immunopathology that is seen.1
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 additionalpossible mechanism for the cytokine release syndrome, relatedto Fc-receptor binding. Species differ greatly with respectto the number of Fc-receptor genes and specific cell-type expressionpatterns. We really do not understand the differences betweennonhuman primates and humans with respect to the diversity ofFc receptors, and we lack information to make cross-speciescomparisons of the binding of human IgG subclasses to Fc receptorsin nonhuman primates.1 There is a need for better models toaddress these issues. It should be noted that differences inboth the antibody subclass and the glycosylation status of theantibody influence the profile of Fc-receptor binding. In addition,human IgG4 has a low level of binding to Fc receptors but isnot a nonbinder. Clearly, it is important to consider the natureof the Fc portion of antibodies as they are developed for clinicaluse 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 SanFrancisco, CA 94143
References
Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin resulting fron Fc sialylation. Science 2006;313:670-673. [Free Full Text]
Nimmerjahn F, Ravetch JV. Fc gamma receptors: old friends and new family members. Immunity 2006;24:19-28. [CrossRef][Web of Science][Medline]
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