HuM291, A HUMANIZED ANTI-CD3 ANTIBODY, IS IMMUNOSUPPRESSIVE TO T CELLS WHILE EXHIBITING REDUCED MITOGENICITY IN VITRO1

Ms, Cole; Ke, Stellrecht; Jd, Shi; Homola, Margit; Dh, Hsu; Anasetti, Claudio; Vásquez, Maximiliano; Jy, Tso

doi:10.1097/00007890-199908270-00020

Cited by 74 publications

(39 citation statements)

References 39 publications

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“…All three mAbs bind to human CD3⑀, but they have different variable region sequences (5,18). Using the murine DNA sequences derived from OKT3 and M291 hybridomas, a panel of genetically engineered anti-CD3 mAbs was produced (5, 7).…”

Section: Anti-cd3 Mabsmentioning

confidence: 99%

“…Non-FcR-binding anti-CD3 mAbs are unable to activate resting T cells (5,7). In this study, we show that non-FcR-binding anti-CD3 mAbs are especially potent at inducing apoptosis selectively in activated T cells.…”

Section: Figurementioning

confidence: 99%

“…A second generation of genetically engineered anti-CD3 mAbs has been developed not only by grafting complementarity-determining regions (CDRs) 3 of murine anti-CD3 mAb into human IgG sequences (2)(3)(4)(5), but also by introducing non-FcR-binding mutations into the Fc (6,7). Humanization of the mAb results in decreased immunogenicity and improved mAb half-life.…”

mentioning

confidence: 99%

“…Humanization of the mAb results in decreased immunogenicity and improved mAb half-life. Furthermore, non-FcR-binding mAbs do not activate resting T cells (5,(7)(8)(9) and have limited potential for inducing cytokine release and acute toxicity in vivo (10 -12). Based on preclinical data in mice, we have been interested in the possibility that such mAbs might provide improved immunosuppression by inducing apoptosis of Ag-activated T cells (13).…”

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confidence: 99%

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Non-Fc Receptor-Binding Humanized Anti-CD3 Antibodies Induce Apoptosis of Activated Human T Cells

Carpenter

Pavlovic

Tso

et al. 2000

The Journal of Immunology

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Human trials in organ allografts have demonstrated that murine anti-CD3 mAbs are immunosuppressive. By mimicking Ag, anti-CD3 can produce T cell activation, anergy, or death. Activation of resting T cells in vivo results in dose-limiting cytokine release and is caused by Ab-mediated cross-linking of T cells and Fcγ receptor (FcR)-bearing cells. With the goal of minimizing cytokine-induced toxicity, anti-CD3 have been engineered to lower Fc binding avidity. Preclinical murine studies have indicated that non-FcR-binding anti-CD3 can induce apoptosis of Ag-activated T cells. Since induction of T cell apoptosis may be an important mechanism of immunosuppression by anti-CD3, we tested whether Fc mutations affect the ability of anti-human CD3 to induce apoptosis of activated T cells. We compared wild-type murine anti-CD3, M291, and OKT3 and their humanized, FcR- and non-FcR-binding structural variants in quantitative assays of T cell apoptosis. Non-FcR-binding variants produced more sustainable phosphorylation of extracellular signal-regulated kinase-2, greater release of IFN-γ, and more effectively caused activation-dependent T cell apoptosis. Non-FcR-binding variants dissociated more quickly from the T cell surface and caused less internalization of the TCR, which then remained available in greater abundance on the cell surface for signaling. Cross-linking of non-FcR-binding variants by antiglobulin enhanced TCR internalization and minimized induction of T cell apoptosis. We conclude that non-FcR-binding, humanized anti-CD3 have improved ability to induce apoptosis of activated T cells, presumably by allowing durable expression of the TCR and sustained signaling.

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Section: Anti-cd3 Mabsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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confidence: 99%

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Non-Fc Receptor-Binding Humanized Anti-CD3 Antibodies Induce Apoptosis of Activated Human T Cells

Carpenter

Pavlovic

Tso

et al. 2000

The Journal of Immunology

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“…9 Visilizumab (HuM291, Nuvion, Plymouth, MN) is a novel non-FcR-binding anti-CD3 monoclonal antibody (mAb) directed against the invariant CD3⑀ chain of the TCR. 10 Its human IgG2 isotype confers the longest in vivo half-life among all human IgGs and reduces its ability to activate human complement or to interact with type I and III FcRs. Engineered mutations within the IgG2 Fc at amino acid residues 234 and 237 (Val3Ala) confer the inability to bind type II FcRs.…”

Section: Introductionmentioning

confidence: 99%

A humanized non–FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease

Carpenter

Appelbaum

Corey

et al. 2002

Blood

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161

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Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fc␥-receptors, and ability to induce apoptosis selectively in activated T cells. To test pharmacokinetics, safety, and immunosuppressive activity of visilizumab, 17 patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD) were enrolled in a phase 1 study. Six patients were given 7 doses of visilizumab (

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Nuclear Medicine Imaging of Inflammatory Diseases

Chianelli

Malviya

Glaudemans

2013

Diagnostic Imaging of Infections and Inflammatory Diseases

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HuM291, A HUMANIZED ANTI-CD3 ANTIBODY, IS IMMUNOSUPPRESSIVE TO T CELLS WHILE EXHIBITING REDUCED MITOGENICITY IN VITRO1

Abstract: When evaluated in vivo, HuM291 may be an immunosuppressive agent associated with less of the acute toxicity and immunogenicity seen with OKT3 therapy.

Cited by 74 publications

References 39 publications

Non-Fc Receptor-Binding Humanized Anti-CD3 Antibodies Induce Apoptosis of Activated Human T Cells

Non-Fc Receptor-Binding Humanized Anti-CD3 Antibodies Induce Apoptosis of Activated Human T Cells

A humanized non–FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease

Nuclear Medicine Imaging of Inflammatory Diseases

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