Humanized, Nonmitogenic OKT3 Antibody, huOKT3γ(Ala-Ala): Initial Clinical Experience

Woodle, E. Steve; Bluestone, Jeffrey A.; Zivin, Robert A.; Jolliffe, Linda K.; Auger, Julie; Xu, Danlin; Thistlethwaite, J. Richard

doi:10.1016/s0041-1345(98)00278-4

Cited by 32 publications

(19 citation statements)

References 4 publications

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“…The expression of early activation markers, including Leu23 and IL-2R following culture with drug, were reduced compared with culture with OKT3, while the binding and modulation properties of the anti-CD3 mAb and its ability to block cytotoxic T lymphocyte (CTL) activity were similar to OKT3 (21). In a clinical study, the FcR nonbinding anti-CD3 mAb, hOKT3γ1(Ala-Ala) was shown to reverse renal and renal/pancreas allograft rejection in five of seven patients without clinical signs of T cell activation in vivo, consistent with the notion that the anti-CD3 mAb was "non-activating" (22)(23)(24). However, all of these patients were given other immune suppressive agents at the time of drug administration; therefore, the effects of the anti-CD3 mAb on T cell activation could not be determined.…”

supporting

confidence: 57%

“…The cytokine release syndrome involves cross-linking of the mAb through binding to the Fc receptor (FcR), activation of T cells in vivo, and release of IL-6 and TNF-α. In an effort to eliminate the toxicity and the development of human anti-mouse Ab's that occur with OKT3, Xu, Zivin, and Bluestone "humanized" the Ig molecule and substituted alanines for leucines at positions 234 and 235 to render the IgG1 molecule FcR nonbinding (21,22). Initial studies with this drug showed that the mutation resulted in a 3 log-fold reduction in proliferation in vitro compared with OKT3, with decreased production of TNF-α and IL-6.…”

mentioning

confidence: 99%

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

Herold¹,

Burton²,

François³

et al. 2003

J. Clin. Invest.

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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

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supporting

confidence: 57%

mentioning

confidence: 99%

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

Herold¹,

Burton²,

François³

et al. 2003

J. Clin. Invest.

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“…The LL234,235AA mutant of b12 was prepared by oligonucleotide-directed mutagenesis (26) in an effort to reduce Fc␥RI and Fc␥RII binding. A similar mutant of a humanized anti-CD3 mAb has been shown to display a strongly reduced Fc-mediated activation of T cells in vivo (27). The recombinant Abs were expressed in CHO cells and purified by protein A affinity chromatography as described (25).…”

Section: Production Of Recombinant Proteinsmentioning

confidence: 99%

The IgG Fc Contains Distinct Fc Receptor (FcR) Binding Sites: The Leukocyte Receptors FcγRI and FcγRIIa Bind to a Region in the Fc Distinct from That Recognized by Neonatal FcR and Protein A

Wines

Powell

Parren

et al. 2000

The Journal of Immunology

133

122

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The CH2-CH3 interface of the IgG Fc domain contains the binding sites for a number of Fc receptors including Staphylococcal protein A and the neonatal Fc receptor (FcRn). It has recently been proposed that the CH2-CH3 interface also contains the principal binding site for an isoform of the low affinity IgG Fc receptor II (FcγRIIb). The FcγRI and FcγRII binding sites have previously been mapped to the lower hinge and the adjacent surface of the CH2 domain although contributions of the CH2-CH3 interface to binding have been suggested. This study addresses the question whether the CH2-CH3 interface plays a role in the interaction of IgG with FcγRI and FcγRIIa. We demonstrate that recombinant soluble murine FcγRI and human FcγRIIa did not compete with protein A and FcRn for binding to IgG, and that the CH2-CH3 interface therefore appears not to be involved in FcγRI and FcγRIIa binding. The importance of the lower hinge was confirmed by introducing mutations in the proposed binding site (LL234,235AA) which abrogated binding of recombinant soluble FcγRIIa to human IgG1. We conclude that the lower hinge and the adjacent region of the CH2 domain of IgG Fc is critical for the interaction between FcγRIIa and human IgG, whereas contributions of the CH2-CH3 interface appear to be insignificant.

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“…In the first, it was used instead of OKT3 for treatment of patients with graft rejection of renal and renal/pancreas allografts. Its efficacy was found to be similar to OKT3 but with marked reduction in adverse events [60]. This trial provided the first evidence for some T-cell activation in vivo, but without the severe cytokine release syndrome that occurs with OKT3 administration.…”

Section: Monoclonal Antibodies Against T Cellsmentioning

confidence: 70%

Treatment of type 1 diabetes with anti-T-cell agents: From T-cell depletion to T-cell regulation

Glandt

Herold

2004

Curr Diab Rep

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Studies in animal models of type 1 diabetes had suggested that the disease was due to an immune-mediated destruction of insulin-producing cells. As this understanding was developed, clinical trials that were directed against T cells were begun, because these lymphocytes were thought to be the primary mediators of disease. Initial studies used broad-spectrum agents and showed general efficacy in either preventing the loss of insulin secretion or reducing the need for exogenous insulin. Although encouraging, the enthusiasm for this approach waned due to the lack of long-term effects and toxicities. These studies were followed by trials with more specific agents, but the issue of toxicity remained. Newer agents, such as anti-CD3 antibody, are also targeted against T cells but the toxicity and efficacy of modified anti-CD3 antibody, for example, appears to be improved over previously tested agents. In addition, our understanding of the immunologic effects of anti-T-cell agents has evolved. Data now suggest that efficacy and duration of the effects of anti-T-cell drugs can be enhanced when the agents provoke immune modulation rather than depletion of effector cells.

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Humanized, Nonmitogenic OKT3 Antibody, huOKT3γ(Ala-Ala): Initial Clinical Experience

Cited by 32 publications

References 4 publications

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

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

The IgG Fc Contains Distinct Fc Receptor (FcR) Binding Sites: The Leukocyte Receptors FcγRI and FcγRIIa Bind to a Region in the Fc Distinct from That Recognized by Neonatal FcR and Protein A

Treatment of type 1 diabetes with anti-T-cell agents: From T-cell depletion to T-cell regulation

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