The Effect of Aglycosylation on the Immunogenicity of a Humanized Therapeutic Cd3 Monoclonal Antibody

Routledge, E. G.; FALCONER, MARGARET E.; Pope, Heather; Lloyd, I S; Waldmann, Herman

doi:10.1097/00007890-199510270-00015

Cited by 34 publications

(12 citation statements)

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“…TRX1 is a humanized IgG1 Ab recognizing domain 1 of human CD4 further modified by introducing a single amino acid substitution (Asn to Ala) at position 297 in the H chain constant region, thus eliminating a major glycoslyation site necessary for high affinity FcR interactions and complement binding (37)(38)(39). To identify a model species in which to test tolerance induction with TRX1, we screened several non-human primate species, including African green monkey, cynomolgus and rhesus macaque, baboon, and chimpanzee, for cross-reactivity with TRX1.…”

Section: Tolerance Induction Protocolmentioning

confidence: 99%

Induction of Immunological Tolerance/Hyporesponsiveness in Baboons with a Nondepleting CD4 Antibody

Winsor-Hines¹,

Merrill²,

O'Mahony³

et al. 2004

The Journal of Immunology

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Section: Tolerance Induction Protocolmentioning

confidence: 99%

Induction of Immunological Tolerance/Hyporesponsiveness in Baboons with a Nondepleting CD4 Antibody

Winsor-Hines¹,

Merrill²,

O'Mahony³

et al. 2004

The Journal of Immunology

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“…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%

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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“…59 Otelixizumab is pharmacologically active in these transgenic mice, suggesting that the human CD3ε chain can associate with the other chains of the mouse CD3-TCR complex to form a functional hybrid CD3-TCR signaling molecule. 60 In addition, these transgenic mice have been bred onto the non-obese diabetic background such that they spontaneously develop autoimmune insulin-dependent diabetes. 61 Treatment of the mice with otelixizumab induced a durable disease remission dependent on transferable T cell-mediated tolerance and TGF-β.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a surrogate murine antibody to model anti-human CD3 therapies

Dépis

Hatterer

Ballet

et al. 2013

mAbs

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The Effect of Aglycosylation on the Immunogenicity of a Humanized Therapeutic Cd3 Monoclonal Antibody

Cited by 34 publications

References 0 publications

Induction of Immunological Tolerance/Hyporesponsiveness in Baboons with a Nondepleting CD4 Antibody

Induction of Immunological Tolerance/Hyporesponsiveness in Baboons with a Nondepleting CD4 Antibody

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

Characterization of a surrogate murine antibody to model anti-human CD3 therapies

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