A humanized anti-CD3 antibody, HUM291, with low mitogenic activity, mediates complete and reversible T-cell depletion in chimpanzees

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 gamma2 M3 (HuM291; Protein Design Labs, Inc., Mountain View, CA), was engineered wit...

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Bibliographic Details
Published in:	Transplantation Vol. 68; no. 4; pp. 545 - 554
Main Authors:	HSU, D.-H, JIA DONG SHI, HOMOLA, M, ROWELL, T. J, MORAN, J, LEVITT, D, DRUILHET, B, CHINN, Y, BULLOCK, C, KLINGBEIL, C
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott 27-08-1999
Subjects:	Animals Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - genetics Antibodies, Monoclonal - pharmacology Antibody Specificity Antilymphocyte Serum - administration & dosage Antilymphocyte Serum - genetics Antilymphocyte Serum - pharmacology Biological and medical sciences CD3 antigen CD3 Complex - metabolism Female Humans Immunomodulators In Vitro Techniques Lymphocyte Activation Lymphocyte Count Lymphocyte Depletion - methods Male Medical sciences Mice Muromonab-CD3 - pharmacology Mutation Pan troglodytes Pharmacology. Drug treatments Protein Engineering Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - immunology Recombinant Fusion Proteins - pharmacology T-Lymphocytes - immunology Cell culture Antibody Monkey Transplantation Experimental study In vitro Biological activity Immunomodulator In vivo Vertebrata Chemotherapy Mammalia Mononuclear cell Treatment Immunogenicity Animal Immunotherapy T-Lymphocyte Primates Mitogen Pharmacokinetics Humanized antibody
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Summary:	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 gamma2 M3 (HuM291; Protein Design Labs, Inc., Mountain View, CA), was engineered with mutations in the upper CH2 region of the Fc domain. The mutations were intended to reduce affinity for Fcgamma receptors, thought to be relevant to CRS. 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. HuM291 bound to and effectively downmodulated CD3 from chimpanzee PBMCs 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; T cells recovered by Day 28. Anti-HuM291 Abs were observed in only 4 of 12 animals and were transient in 2 of those animals. 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0041-1337 1534-6080
DOI:	10.1097/00007890-199908270-00018