Specific Targeting Immunotherapy of Cancer with Bispecific Antibodies.

Abstract

In order to enhance cell mediated cytotoxicity, bispecific antibodies (BsAbs), molecules combining two or more antibodies with different antigenic specificities, have been developed as new agents for immunotherapy. Our recent studies revealed that simultaneous administration of two kinds of BsAbs (anti-tumor x anti-CD3 plus anti-tumor x anti-CD28) together with lymphokine activated killer cells with a T cell phenotype (T-LAK cells) inhibited growth of human xenotransplanted tumors in severe combined immunodeficient (SCID) mice, while single BsAb was without effect. Three kinds of BsAbs (anti-tumor x anti-CD3, anti-tumor x anti-CD28, anti-tumor x anti-CD2) showed the highest cytotoxicity against tumor cells when given simultaneously with T-LAK cells or peripheral blood mononuclear cells in vitro and in vivo. BsAbs can be preserved for immediate application, while cytotoxic T lymphocytes (CTLs) must be made-to-order, and are time-consuming to prepare. Tumor associated antigens, such as MAGE antigens, SART antigens, MUC1 antigen, c-erbB 2 antigen or cancer/testis antigens can be served to target antigens for BsAb production. By conjugation with antibodies to effector cells (anti-CD3, anti-CD28, anti-CD16, anti-CD64, anti-CD89 or anti-CD2), many kinds of BsAbs can be produced to cover most types of cancers from different organs. Therefore this strategy might be ubiquitously applicable to most malignancies.

Use of trifunctional bispecific antibodies to prevent graft versus host disease induced by allogeneic lymphocytes

“…[1][2][3][4][5] This strategy is based on the assumption that appropriate effector-target cell interaction via a physical contact between immune cells and tumor cells activates cytotoxic mechanisms that lead to an efficient eradication of tumor cells. Many different bispecific antibody formats have been created over the last 20 years with varying quality as to production, in vitro and in vivo efficacy, and recruitment of effector cells including the creation of additional T-cell stimuli.…”

Induction of long-lasting antitumor immunity by concomitant cell therapy with allogeneic lymphocytes and trifunctional bispecific antibody

“…Such trAb can recruit and activate T cells as well as the accessory and natural killer (NK) cells resulting in simultaneous activation of different effector mechanisms, including for example, phagocytosis and perforin/granzyme-mediated antibodydependent cell-cytotoxicity at the tumor site. As such, trAb improve the efficacy of tumor cell eradication in vitro [9,10], as well as in vivo in murine models [11,12], and in human clinical trials [13][14][15]. In the context of allogeneic stem cell transplantation and subsequent immunotherapy with donor lymphocyte infusion, trAb may improve the targeting of tumor cells by immune effector cells while reducing the risk of undesirable reactivity against normal host cells, thus maximizing graft-vs-malignancy effects, while reducing the incidence and severity of graft-vs-host disease (GVHD).…”