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T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct

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Abstract

BscCD19xCD3 is a bispecific single-chain antibody construct with exceptional cytotoxic potency in vitro and in vivo. Here, we have investigated the biological activity of bscCD19xCD3 in chimpanzee, the only animal species identified in which bscCD19xCD3 showed bispecific binding, redirected B-cell lysis and cytokine production comparable to human cells. Pharmacokinetic analysis following 2-h intravenous infusion of 0.06, 0.1 or 0.12 μg/kg of bscCD19xCD3 as part of a dose escalation study in a single female chimpanzee revealed a half-life of approximately 2 h and elimination of the bispecific antibody from circulation within approximately 8 h after the end of infusion. This short exposure to bscCD19xCD3 elicited a transient increase in serum levels of IFNγ, IL-6, IL-2, soluble CD25, and transiently upregulated expression of CD69 and MHC class II on CD8-positive cells. Cytokine release and upregulation of T-cell activation markers were not observed with vehicle controls. A multiple-dose study using 5 weekly doses of 0.1 μg/kg in two animals also showed transient cytokine release and an activation of peripheral T cells with a first-dose effect, accompanied by a transient lymphopenia. While oscillations of T-cell counts were relatively even during repeated treatments, the amplitudes of peripheral B cells declined with every infusion, which was not observed in a vehicle control animal. Our data show that bscCD19xCD3 can be safely administered to chimpanzees at dose levels that cause fully reversible T-cell activation and, despite a very short exposure time, cumulative loss of peripheral B lymphocytes. A clinical trial testing prolonged administration of bscCD19xCD3 (MT103) for improving efficacy is currently ongoing.

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Author notes

  1. Torsten Dreier

    Present address: Ablynx NV, Technologiepark 4, 9052, Zwijnaarde, Belgium

  2. Cornelia Quadt

    Present address: Oncology Business Unit, Novartis AG, WKL-490.1.50, 4002, Basel, Switzerland

Authors and Affiliations

  1. Micromet AG, Staffelseestr. 2, 81477, Munich, Germany

    Bernd Schlereth, Cornelia Quadt, Torsten Dreier, Peter Kufer, Grit Lorenczewski, Nadja Prang, Christian Brandl, Sandra Lippold, Eugen Leo & Patrick A. Baeuerle

  2. Southwest Foundation of Biomedical Research, P.O. Box 760549, San Antonio, TX, 78245-0549, USA

    Kathy Cobb, Kathleen Brasky & Krishna Murthy

  3. Robert-Rössle-Clinic, University Medical Center Charité, Humboldt University of Berlin, and Helios Kliniken Berlin, Lindenberger Weg 80, 13122, Berlin-Buch, Germany

    Ralf Bargou

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  1. Bernd Schlereth
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  14. Patrick A. Baeuerle
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Correspondence to Patrick A. Baeuerle.

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Schlereth, B., Quadt, C., Dreier, T. et al. T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Cancer Immunol Immunother 55, 503–514 (2006). https://doi.org/10.1007/s00262-005-0001-1

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  • DOI: https://doi.org/10.1007/s00262-005-0001-1

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