CD3 directed bispecific antibodies induce increased lymphocyte–endothelial cell interactions in vitro

Abstract

Bispecific antibody (BsMAb) BIS-1 has been developed to redirect the cytolytic activity of cytotoxic T lymphocytes (CTL) to epithelial glycoprotein-2 (EGP-2) expressing tumour cells. Intravenous administration of BIS-1 F(ab′) 2 to carcinoma patients in a phase I/II clinical trial, caused immunomodulation as demonstrated by a rapid lymphopenia prior to a rise in plasma tumour necrosis factor-α and interferon-γ levels. Yet, no lymphocyte accumulation in the tumour tissue and no anti-tumour effect could be observed. These data suggest a BsMAb-induced lymphocyte adhesion to blood vessel walls and/or generalized redistribution of the lymphocytes into tissues. In this study, we describe the effects of BIS-1 F(ab′) 2 binding to peripheral blood mononuclear cells (PBMC) on their capacity to interact with resting endothelial cells in vitro. Resting and pre-activated PBMC exhibited a significant increase in adhesive interaction with endothelial cells when preincubated with BIS-1 F(ab′) 2 , followed by an increase in transendothelial migration (tem). Binding of BIS-1 F(ab′) 2 to PBMC affected the expression of a number of adhesion molecules involved in lymphocyte adhesion/migration. Furthermore, PBMC preincubated with BIS-1 F(ab′) 2 induced the expression of endothelial cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 during adhesion/tem. These phenomena were related to the CD3 recognizing antibody fragment of the BsMAb and dependent on lymphocyte–endothelial cell contact. Possibly, in patients, the BIS-1 F(ab′) 2 infusion induced lymphopenia is a result of generalized activation of endothelial cells, leading to the formation of a temporary sink for lymphocytes. This process may distract the lymphocytes from homing to the tumour cells, and hence prevent the occurrence of BIS-1 F(ab′) 2 – CTL-mediated tumour cell lysis. © 2000 Cancer Research Campaign

Effective Relief of Malignant Ascites in Patients with Advanced Ovarian Cancer by a Trifunctional Anti-EpCAM × Anti-CD3 Antibody: A Phase I/II Study

“…The observed transient lymphocyte decrease has been reported in other studies, suggesting that infused bispecific antibodies induce a passive interaction of lymphocytes with endothelial cells, followed by a generalized redistribution of lymphocytes into tissues (27). As in studies in bone marrow/ stem cell transplantation, a restoration of peripheral lymphocytes after cytotoxic damage due to high-dose chemotherapy took 1 to 6 months (28,29), the transient decrease of lymphocytes for 1 to maximally 8 days is most probably due to a shift of the lymphocytes into another compartment, where they are not detectable by conventional blood sampling measures.…”

Treatment of Malignant Pleural Effusion With the Trifunctional Antibody Catumaxomab (Removab) (Anti-EpCAM×Anti-CD3)

“…Similar phenomenon have been described in literature where an antibody-mediated activation led to the up-regulation of adhesion molecules on white blood cells and migration of peripheral lymphocytes into the tissue and possibly into the tumor. 32 Transient leukocytosis with neutrophilia and lymphocytopenia are also regularly observed in this trial and also in other trials. 28 In the majority of cases, these changes were without clinical signs and symptoms (no increase in infectious diseases was observed) and in general fully reversible.…”

Gamma knife radiosurgery for brain metastasis of nonsmall cell lung cancer: Is there a difference in outcome between morning and afternoon treatment?

“…Transiently increased liver parameters were typically observed, which can be partially explained by catumaxomab binding to EpCAM+ bile duct cells and the release of cytokines 37. The transient decrease in the peripheral lymphocyte count might be the result of migration of lymphocytes into the tissue and possibly to the tumor, mediated by upregulation of adhesion molecules on white blood cells after antibody‐mediated activation 38…”