ADOPTIVE IMMUNOTHERAPY WITH BISPECIFIC ANTIBODIES - TARGETING THROUGH MACROPHAGES

We report on two applications of bispecific antibodies to enhance the antitumoral function of human macrophages: (1) use of rhuIFN-gamma (recombinant human IFN-gamma) encapsulated in human red blood cells coated with anti-Fc-gamma-RI/anti-RhD+ bispecific antibodies to target and to activate human macrophages; encapsulated rhuIFN-gamma was more potent than free IFN-gamma in activating mature macrophages in vitro, demonstrating the efficacy of this delivery system to initiate in situ activation of macrophages and also to maintain a high antitumoral efficacy of macrophages with less side effects than after systemic injection of IFN-gamma; (2) targeting of activated macrophages to tumours by bispecific antibodies directed against macrophage Fc-gamma-RI and against human adenocarcinoma antigen; differentiated human macrophages became cytotoxic for human adenocarcinoma in vitro and in vivo (tumours implanted in nude mice) when activated by rhuIFN-gamma; this effect was increased in the presence of bispecific antibodies. These two approaches were aimed at increasing the efficacy of cellular immunotherapies using activated macrophages as effector cells (macrophage-activated killer, or MAK), an adoptive therapy which we have developed. Bispecific antibodies could increase specific homing and activation of cytotoxic MAK effectors at tumour sites.