Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors

Douglas J. Norman, Flavio Vincenti, Angelo M DeMattos, John M. Barry, Daniel J. Levitt, Nancy I. Wedel, Mauricio Maia, Susan E. Light

Research output: Contribution to journalArticle

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Abstract

Background. HuM291 is a humanized anti-CD3 monoclonal antibody engineered to reduce binding to Fcγ receptors and complement fixation. HUM291 has a long serum half-life and mediated profound depletion of circulating T cells in chimpanzees; HuM291 also has significantly less mitogenic and cytokine-releasing activity than OKT3 in vitro. Methods. A phase I dose-escalation study was conducted in 15 end-stage renal disease patients scheduled for renal allografts from living donors. Patients received one i.v. HuM291 injection before transplantation. Five doses were tested: 0.015 μg/kg, 0.15 μg/kg, 0.0015 mg/kg, 0.0045 mg/kg, and 0.015 mg/kg. Patients were followed for adverse events, laboratory abnormalities, serum cytokine levels, pharmacokinetics, and CD2+, CD3+, CD4+, and CD8+ T cell counts. Results. HuM291 was well tolerated; most adverse events were mild to moderate in severity and included headache, nausea, chills, and fever. These occurred within the first few hours after HuM291 administration, resolved within 24 to 48 hr, and were likely related to cytokine release. In general, peak tumor necrosis factor-α, interferon-γ, and interleukin-6 levels were detected 1 to 6 hr postdosing only at the three highest doses and were generally undetectable by 24-hr postdosing. Serious adverse events possibly related to HuM291 included clotting of a fistula (two patients), chemical cellulitis (one patient), and increased serum creatinine/decreased hematocrit (one patient). At doses ≥0.0015 mg/kg (0.1 mg/70 kg), HuM291 induced rapid, marked depletion of peripheral T cells within 2 hr; duration of T cell depletion was dose dependent. At the two highest dose levels, T cells remained depleted for approximately 1 week. Conclusions. A single HuM291 dose rapidly depleted circulating T cells in a dose-dependent manner and was associated with only mild to moderate symptoms of cytokine release.

Original languageEnglish (US)
Pages (from-to)1707-1712
Number of pages6
JournalTransplantation
Volume70
Issue number12
StatePublished - Dec 27 2000
Externally publishedYes

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Antibodies, Monoclonal, Humanized
Living Donors
Allografts
Anti-Idiotypic Antibodies
Kidney
T-Lymphocytes
Cytokines
Serum
visilizumab
Muromonab-CD3
Chills
Cellulitis
Pan troglodytes
Fc Receptors
Hematocrit
Nausea
Interferons
Chronic Kidney Failure
Fistula
Headache

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Norman, D. J., Vincenti, F., DeMattos, A. M., Barry, J. M., Levitt, D. J., Wedel, N. I., ... Light, S. E. (2000). Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors. Transplantation, 70(12), 1707-1712.

Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors. / Norman, Douglas J.; Vincenti, Flavio; DeMattos, Angelo M; Barry, John M.; Levitt, Daniel J.; Wedel, Nancy I.; Maia, Mauricio; Light, Susan E.

In: Transplantation, Vol. 70, No. 12, 27.12.2000, p. 1707-1712.

Research output: Contribution to journalArticle

Norman, DJ, Vincenti, F, DeMattos, AM, Barry, JM, Levitt, DJ, Wedel, NI, Maia, M & Light, SE 2000, 'Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors', Transplantation, vol. 70, no. 12, pp. 1707-1712.
Norman, Douglas J. ; Vincenti, Flavio ; DeMattos, Angelo M ; Barry, John M. ; Levitt, Daniel J. ; Wedel, Nancy I. ; Maia, Mauricio ; Light, Susan E. / Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors. In: Transplantation. 2000 ; Vol. 70, No. 12. pp. 1707-1712.
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abstract = "Background. HuM291 is a humanized anti-CD3 monoclonal antibody engineered to reduce binding to Fcγ receptors and complement fixation. HUM291 has a long serum half-life and mediated profound depletion of circulating T cells in chimpanzees; HuM291 also has significantly less mitogenic and cytokine-releasing activity than OKT3 in vitro. Methods. A phase I dose-escalation study was conducted in 15 end-stage renal disease patients scheduled for renal allografts from living donors. Patients received one i.v. HuM291 injection before transplantation. Five doses were tested: 0.015 μg/kg, 0.15 μg/kg, 0.0015 mg/kg, 0.0045 mg/kg, and 0.015 mg/kg. Patients were followed for adverse events, laboratory abnormalities, serum cytokine levels, pharmacokinetics, and CD2+, CD3+, CD4+, and CD8+ T cell counts. Results. HuM291 was well tolerated; most adverse events were mild to moderate in severity and included headache, nausea, chills, and fever. These occurred within the first few hours after HuM291 administration, resolved within 24 to 48 hr, and were likely related to cytokine release. In general, peak tumor necrosis factor-α, interferon-γ, and interleukin-6 levels were detected 1 to 6 hr postdosing only at the three highest doses and were generally undetectable by 24-hr postdosing. Serious adverse events possibly related to HuM291 included clotting of a fistula (two patients), chemical cellulitis (one patient), and increased serum creatinine/decreased hematocrit (one patient). At doses ≥0.0015 mg/kg (0.1 mg/70 kg), HuM291 induced rapid, marked depletion of peripheral T cells within 2 hr; duration of T cell depletion was dose dependent. At the two highest dose levels, T cells remained depleted for approximately 1 week. Conclusions. A single HuM291 dose rapidly depleted circulating T cells in a dose-dependent manner and was associated with only mild to moderate symptoms of cytokine release.",
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T1 - Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors

AU - Norman, Douglas J.

AU - Vincenti, Flavio

AU - DeMattos, Angelo M

AU - Barry, John M.

AU - Levitt, Daniel J.

AU - Wedel, Nancy I.

AU - Maia, Mauricio

AU - Light, Susan E.

PY - 2000/12/27

Y1 - 2000/12/27

N2 - Background. HuM291 is a humanized anti-CD3 monoclonal antibody engineered to reduce binding to Fcγ receptors and complement fixation. HUM291 has a long serum half-life and mediated profound depletion of circulating T cells in chimpanzees; HuM291 also has significantly less mitogenic and cytokine-releasing activity than OKT3 in vitro. Methods. A phase I dose-escalation study was conducted in 15 end-stage renal disease patients scheduled for renal allografts from living donors. Patients received one i.v. HuM291 injection before transplantation. Five doses were tested: 0.015 μg/kg, 0.15 μg/kg, 0.0015 mg/kg, 0.0045 mg/kg, and 0.015 mg/kg. Patients were followed for adverse events, laboratory abnormalities, serum cytokine levels, pharmacokinetics, and CD2+, CD3+, CD4+, and CD8+ T cell counts. Results. HuM291 was well tolerated; most adverse events were mild to moderate in severity and included headache, nausea, chills, and fever. These occurred within the first few hours after HuM291 administration, resolved within 24 to 48 hr, and were likely related to cytokine release. In general, peak tumor necrosis factor-α, interferon-γ, and interleukin-6 levels were detected 1 to 6 hr postdosing only at the three highest doses and were generally undetectable by 24-hr postdosing. Serious adverse events possibly related to HuM291 included clotting of a fistula (two patients), chemical cellulitis (one patient), and increased serum creatinine/decreased hematocrit (one patient). At doses ≥0.0015 mg/kg (0.1 mg/70 kg), HuM291 induced rapid, marked depletion of peripheral T cells within 2 hr; duration of T cell depletion was dose dependent. At the two highest dose levels, T cells remained depleted for approximately 1 week. Conclusions. A single HuM291 dose rapidly depleted circulating T cells in a dose-dependent manner and was associated with only mild to moderate symptoms of cytokine release.

AB - Background. HuM291 is a humanized anti-CD3 monoclonal antibody engineered to reduce binding to Fcγ receptors and complement fixation. HUM291 has a long serum half-life and mediated profound depletion of circulating T cells in chimpanzees; HuM291 also has significantly less mitogenic and cytokine-releasing activity than OKT3 in vitro. Methods. A phase I dose-escalation study was conducted in 15 end-stage renal disease patients scheduled for renal allografts from living donors. Patients received one i.v. HuM291 injection before transplantation. Five doses were tested: 0.015 μg/kg, 0.15 μg/kg, 0.0015 mg/kg, 0.0045 mg/kg, and 0.015 mg/kg. Patients were followed for adverse events, laboratory abnormalities, serum cytokine levels, pharmacokinetics, and CD2+, CD3+, CD4+, and CD8+ T cell counts. Results. HuM291 was well tolerated; most adverse events were mild to moderate in severity and included headache, nausea, chills, and fever. These occurred within the first few hours after HuM291 administration, resolved within 24 to 48 hr, and were likely related to cytokine release. In general, peak tumor necrosis factor-α, interferon-γ, and interleukin-6 levels were detected 1 to 6 hr postdosing only at the three highest doses and were generally undetectable by 24-hr postdosing. Serious adverse events possibly related to HuM291 included clotting of a fistula (two patients), chemical cellulitis (one patient), and increased serum creatinine/decreased hematocrit (one patient). At doses ≥0.0015 mg/kg (0.1 mg/70 kg), HuM291 induced rapid, marked depletion of peripheral T cells within 2 hr; duration of T cell depletion was dose dependent. At the two highest dose levels, T cells remained depleted for approximately 1 week. Conclusions. A single HuM291 dose rapidly depleted circulating T cells in a dose-dependent manner and was associated with only mild to moderate symptoms of cytokine release.

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