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Titolo:
A humanized anti-CD3 antibody, HuM291, with low mitogenic activity, mediates complete and reversible T-cell depletion in chimpanzees
Autore:
Hsu, DH; Shi, JD; Homola, M; Rowell, TJ; Moran, J; Levitt, D; Druilhet, B; Chinn, J; Bullock, C; Klingbeil, C;
Indirizzi:
Prot Design Labs Inc, Fremont, CA 94555 USA Prot Design Labs Inc Fremont CA USA 94555 Labs Inc, Fremont, CA 94555 USA New Iberia Res Ctr, New Iberia, LA 70560 USA New Iberia Res Ctr New Iberia LA USA 70560 Ctr, New Iberia, LA 70560 USA
Titolo Testata:
TRANSPLANTATION
fascicolo: 4, volume: 68, anno: 1999,
pagine: 545 - 554
SICI:
0041-1337(19990827)68:4<545:AHAAHW>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
OKT3 MONOCLONAL-ANTIBODY; RENAL-ALLOGRAFT REJECTION; KIDNEY-TRANSPLANT RECIPIENTS; RANDOMIZED PROSPECTIVE TRIAL; ISOTYPE SWITCH VARIANTS; TUMOR NECROSIS FACTOR; MUROMONAB CD3; ANTIGENIC MODULATION; ORTHOCLONE OKT3; SERUM LEVELS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Klingbeil, C Prot Design Labs Inc, 34801 Campus Dr, Fremont, CA 94555 USA Prot Design Labs Inc 34801 Campus Dr Fremont CA USA 94555 USA
Citazione:
D.H. Hsu et al., "A humanized anti-CD3 antibody, HuM291, with low mitogenic activity, mediates complete and reversible T-cell depletion in chimpanzees", TRANSPLANT, 68(4), 1999, pp. 545-554

Abstract

Background. An anti-CD3 antibody that reduces cytokine release syndrome (CRS) while maintaining immunosuppression would be a major advance in the treatment of acute allograft rejection. A humanized (Hu) anti-CD3 IgG2 Ab, HuM291 gamma 2 M3 (HuM291; Protein Design Labs, Inc., Mountain View, CA), was engineered with mutations in the upper C(H)2 region of the Fc domain. The mutations were intended to reduce affinity for Fc gamma receptors, thought to be relevant to CRS,Methods. In vitro studies using chimpanzee peripheral blood mononuclear cells (PBMCs) were conducted to characterize HuM291 and to establish an animal model. A multidose study was conducted in chimpanzees to evaluate the safety, pharmacokinetics, immunomodulatory activity, and immunogenicity of HuM291, when administered at doses ranging from 0.1 to 10 mg. Results. HuM291 bound to and effectively downmodulated CD3 from chimpanzeePBMCs and stimulated substantially less cytokine secretion and proliferation of chimpanzee PBMCs compared with OKT3 (Orthoclone OKT3; Ortho Pharmaceutical Corp., Raritan, NJ). Multiple doses of HuM291 (0,1, 1.0, or 10 mg/ dose) were not associated with adverse events, signs of toxicity, or CRS, despite cytokine release. HuM291 exhibited a long elimination t1/2 (81.5 hr) and, after three 10-mg doses, sustained serum concentrations > 1000 ng/ml were maintained for 1 week. Multiple 10-mg doses induced complete depletion of circulating CD2(+)CD3(+) T cells for up to 10 days after the last dose; Tcells recovered by Day 28. Anti-HuM291 Abs were observed in only 4 of 12 animals and were transient in 2 of those animals. Conclusions. In vitro, HuM291 is substantially less mitogenic than OKT3. In chimpanzees, HuM291 effectively depleted peripheral T cells without eliciting clinical signs of CRS, and recovered T cells were functionally normal.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/09/20 alle ore 10:00:24