Reduction of EGP‐2‐positive pulmonary metastases by bispecific‐antibody‐redirected T cells in an immunocompetent rat model

Abstract

Effectiveness of bispecific-monoclonal-antibody (BsMAb)-mediated cellular anti-tumour activity was evaluated in vitro and in vivo in relation to the additional need for T-cell activation in a new immunocompetent rat tumour model. L37 tumour cells, derived from a squamous-cell carcinoma of the lung of Wag/Rij rats, were transfected with the cDNA coding for the human 38-kDa transmembrane pan-carcinoma-associated antigen EGP-2. Intravenous inoculation of EGP-2-positive L37 cells resulted in a rapid outgrowth of EGP-2-positive tumour nodules in the lungs. A BsMAb BIS-19, recognizing EGP-2 on the transfected tumour cells and the T-cell receptor of the rat, was made and allowed specific lysis of EGP-2-transfected L37 tumour cells by activated rat T lymphocytes in vitro. In vivo T-cell activation, assessed by up-regulation of IL-2-receptor expression, could be induced by daily injection of rat rIL-2. Intravenous treatment of tumour-bearing EGP-2-positive L37 tumour with BIS-19 together with rat rIL-2 resulted in almost complete disappearance of established tumour. In contrast, animals treated with BIS-19 alone, IL-2 alone or a combination of anti-EGP-2, anti-TcR and IL-2 showed much less or no tumour reduction. These results show effectiveness of systemic treatment with BsMAbs to induce anti-tumour activity in established tumours. Immune activation prior to or during treatment with BsMAbs, as achieved with IL-2, appears to be a prerequisite for successful treatment.

Targeting T cells against brain tumors with a bispecific ligand-antibody conjugate

“…40 days from day 80 to 120 for treated mice). Previous reports have demonstrated tumor infiltrating lymphocytes in established solid tumors after bispecific antibody treatment (Thibault et al, 1996), but few have demonstrated a reduction in solid tumor growth or prolongation of survival (Kroesen et al, 1995). The present findings are noteworthy given the difficulties posed by the bloodbrain barrier and the relative immune privilege of the brain.…”

Tumor-growth inhibition with bispecific antibody fragments in a syngeneic mouse melanoma model: The role of targeted T-cell co-stimulationvia CD28

“…I.v., rather than i.p., inoculation of a larger number of B16 tumor cells results in an entirely different pattern of tumor growth, with animals dying from extensive pulmonary metastasis. Marked inhibition of pulmonary metastasis after treatment with bsAbs has been reported in 2 different mouse models (Penna et al, 1994; Bakacs et al, 1995; Belen‐Moreno et al, 1995) and 1 rat model (Kroesen et al, 1995). However, in the one study reporting survival data, the survival time of animals treated with anti‐tumor × anti‐CD3 bsFab 2 was only marginally increased (Bakacs et al, 1995).…”

Engineering Bispecific Antibodies That Target ERBB-2 on Breast Cancer Cells

“…40 days from day 80 to 120 for treated mice). Previous reports have demonstrated tumor infiltrating lymphocytes in established solid tumors after bispecific antibody treatment (Thibault et ah, 1996), but few have demonstrated a reduction in solid tumor growth or prolongation of survival (Kroesen et al, 1995). The present findings are noteworthy given the difficulties posed by the bloodbrain barrier and the relative immune privilege of the brain.…”