RESUMO
We assessed the tolerability and antitumor activity of solitomab, a bispecific T-cell engager (BiTE®) antibody construct targeting epithelial cell adhesion molecule (EpCAM). Patients with relapsed/refractory solid tumors not amenable to standard therapy received solitomab as continuous IV infusion in a phase 1 dose-escalation study with six different dosing schedules. The primary endpoint was frequency and severity of adverse events (AEs). Secondary endpoints included pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. Sixty-five patients received solitomab at doses between 1 and 96 µg/day for ≥28 days. Fifteen patients had dose-limiting toxicities (DLTs): eight had transient abnormal liver parameters shortly after infusion start or dose escalation (grade 3, n = 4; grade 4, n = 4), and one had supraventricular tachycardia (grade 3); all events resolved with solitomab discontinuation. Six patients had a DLT of diarrhea: four events resolved (grade 3, n = 3; grade 4, n = 1), one (grade 3) was ongoing at the time of treatment-unrelated death, and one (grade 3) progressed to grade 5 after solitomab discontinuation. The maximum tolerated dose was 24 µg/day. Overall, 95% of patients had grade ≥3 treatment-related AEs, primarily diarrhea, elevated liver parameters, and elevated lipase. Solitomab half-life was 4.5 hours; serum levels plateaued within 24 hours. One unconfirmed partial response was observed. In this study of a BiTE® antibody construct targeting solid tumors, treatment of relapsed/refractory EpCAM-positive solid tumors with solitomab was associated with DLTs, including severe diarrhea and increased liver enzymes, which precluded dose escalation to potentially therapeutic levels.
RESUMO
MuS110 is a BiTE antibody bispecific for murine EpCAM (CD326) and murine CD3. A recent study has shown that microS110 has significant anti tumor activity at well-tolerated doses as low as 5 microg/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 microS110 at higher doses. Escalation to 50 microg/kg microS110 caused in mice transient loss of body weight, and transient piloerection, hypomotility, hypothermia and diarrhoea. These clinical signs coincided with serum peaks of TNF-alpha, IL-6, IL-2, IFN-gamma 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 microS110 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 microS110 dramatically increased the tolerability of animals up to at least 500 microg/kg of the BiTE antibody. This high tolerability to microS110 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 microg/kg microS110 for 28 days. In summary, these observations suggest that side effects of microS110 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.