Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3γ1(Ala-Ala)
Kevan C. Herold, … , Mariela Glandt, Jeffrey A. Bluestone
Kevan C. Herold, … , Mariela Glandt, Jeffrey A. Bluestone
Published February 1, 2003
Citation Information: J Clin Invest. 2003;111(3):409-418. https://doi.org/10.1172/JCI16090.
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Article Metabolism

Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3γ1(Ala-Ala)

Abstract

Dimeric Fc receptor (FcR) nonbinding anti-CD3 antibodies have been developed to minimize toxicities associated with classical anti-CD3 monoclonal antibodies (e.g., OKT3). Studies with murine analogs of non-FcR–binding antibodies have shown reduced mitogenicity compared to OKT3. In a trial of an FcR nonbinding humanized anti-CD3 mAb hOKT3γ1(Ala-Ala) for treatment of patients with type 1 diabetes, we found significant increases in IL-10 and IL-5 in the serum of 63% and 72% of patients, respectively, and TNF-α and IL-6 levels that were lower than those previously reported following OKT3 therapy. The activation signal delivered by hOKT3γ1(Ala-Ala) was associated with calcium signaling and cytokine production by previously activated human cells in vitro. However, the production of IL-10, compared to IFN-γ on a molar basis, was greater after culture with hOKT3γ1(Ala-Ala) than with OKT3. Flow cytometric studies confirmed that OKT3 induced IFN-γ and IL-10 production, but hOKT3γ1(Ala-Ala) induced only detectable IL-10 production in CD45RO+ cells. Moreover, in vivo, we found IL-10+CD4+ T cells after drug treatment. These cells were heterogeneous but generally CD45RO+, CTLA-4–, and expressed CCR4. A subgroup of these cells expressed TGF-β. Thus, the non-FcR binding anti-CD3 mAb, hOKT3γ1(Ala-Ala) delivers an activation signal to T cells that is quantitatively and qualitatively different from OKT3. It leads to the generation of T cells that might inhibit the autoimmune response and may be involved in the beneficial effect on β cell destruction in Type 1 diabetes.

Authors

Kevan C. Herold, Joshua B. Burton, Fleur Francois, Ena Poumian-Ruiz, Mariela Glandt, Jeffrey A. Bluestone

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Figure 1

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Cytokine levels following administration of hOKT3γ1(Ala-Ala). The levels...
Cytokine levels following administration of hOKT3γ1(Ala-Ala). The levels of cytokines in serum were measured as described in Methods. The average (± SEM) of the highest level of cytokines following drug administration on days 1, 2, 5, and 6 (first 12 patients) or days 1, 2, 3, and 4 (patients 9–20) for each patient in the two dosing protocols (see Methods) are shown. ptl, protocol.