EFFECTIVE INTRODUCTION OF T-CELL COSTIMULATORY MOLECULES INTO VIRUS MODIFIED TUMOR-CELL VACCINES BY MODIFICATION WITH BISPECIFIC ANTIBODIES

This report describes the generation of bispecific antibodies which bi nd with one arm to virus modified tumor cell vaccines and introduce wi th the other arm anti-murine CD28 T cell costimulatory molecules. This is an effective alternative to somatic gene therapy strategies using genes coding for ligands of CD28 such as CD80 (B7-1) or CD86 (B7-2). W hile these B7 molecules interact not only with CD28 but also with CLTA -4, thereby generating a negative signal, agonistic anti CD28 antibodi es only bind to CD28 and therefore deliver only positive costimulatory signals. The new bispecific antibody (bsAb) HN x CD28 allows the intr oduction of anti-CD28 antibodies into the tumor cell vaccine ATV-NDV, an autologous tumor cell vaccine already modified by infection with Ne wcastle Disease Virus (NDV). The bsAb HN x CD28 attaches with its anti -HN binding site to the NDV derived hemagglutinin-neuraminidase (HN) m olecule which serves as a common foreign anchoring molecule in the vac cine. NDV infected tumor cells which were further modified with HN x C D28 on their cell surface (bs-vaccine), showed increased T cell stimul atory capacity in vitro. This was revealed by augmented proliferation as well as augmented CTL activity. When syngeneic mice were injected w ith aggressive murine ESb lymphoma cells which were infected with NDV and further modified with the bsAb HN x CD28, delayed tumor developmen t and prolonged survival was observed in comparison to respective cont rols.