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Therapeutic window of an EpCAM/CD3-specific BiTE antibody in mice is determined by a subpopulation of EpCAM-expressing lymphocytes that is absent in humans

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Abstract

MuS110 is a BiTE antibody bispecific for murine EpCAM (CD326) and murine CD3. A recent study has shown that muS110 has significant anti tumor activity at well-tolerated doses as low as 5 μg/kg in orthotopic breast and lung cancer models (Amann et al. in Cancer Res 68:143–151, 2008). Here, we have explored the safety profile of muS110 at higher doses. Escalation to 50 μg/kg muS110 caused in mice transient loss of body weight, and transient piloerection, hypomotility, hypothermia and diarrhoea. These clinical signs coincided with serum peaks of TNF-α, IL-6, IL-2, IFN-γ and IL-4, and an increase of surface markers for T cell activation. Because activation of T cells in response to BiTE antibodies is typically dependent on target cells, we analyzed mouse blood for the presence of EpCAM+ cells. Various mouse strains presented with a subpopulation of 2–3% EpCAM+ blood cells, mostly B and T lymphocytes, which was not detected in human blood samples. In vitro experiments in which the number of EpCAM+ cells in blood samples was either reduced or increased suggested that both T cell activation and cytokine release in response to muS110 was dependent on the number of target-expressing cells. In support for a role of EpCAM+ lymphocytes in the observed side effects, reduction of EpCAM+ blood cells in mice via a low-dose pre treatment with muS110 dramatically increased the tolerability of animals up to at least 500 μg/kg of the BiTE antibody. This high tolerability to muS110 occurred in the presence of non-compromised T cells. No damage to EpCAM+ epithelial tissues was evident from histopathological examination of animals daily injected with 100 μg/kg muS110 for 28 days. In summary, these observations suggest that side effects of muS110 in mice were largely caused by an acute T cell activation that was triggered by a subpopulation of EpCAM+ lymphocytes. Because humans have extremely low numbers of EpCAM+ cells in blood, this toxicity of an EpCAM-specific BiTE may be specific for mice.

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Authors and Affiliations

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

    Maria Amann, Matthias Friedrich, Petra Lutterbuese, Eva Vieser, Grit Lorenczewski, Laetitia Petersen, Klaus Brischwein, Peter Kufer, Roman Kischel, Patrick A. Baeuerle & Bernd Schlereth

  2. Micromet, Inc., 6707 Democracy Blvd., Suite 505, Bethesda, MD, 20817, USA

    Maria Amann, Matthias Friedrich, Petra Lutterbuese, Eva Vieser, Grit Lorenczewski, Laetitia Petersen, Klaus Brischwein, Peter Kufer, Roman Kischel, Patrick A. Baeuerle & Bernd Schlereth

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  1. Maria Amann
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Correspondence to Patrick A. Baeuerle.

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M. Amann and M. Friedrich contributed equally to this work.

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Amann, M., Friedrich, M., Lutterbuese, P. et al. Therapeutic window of an EpCAM/CD3-specific BiTE antibody in mice is determined by a subpopulation of EpCAM-expressing lymphocytes that is absent in humans. Cancer Immunol Immunother 58, 95–109 (2009). https://doi.org/10.1007/s00262-008-0529-y

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