Immunocytokines and bispecific antibodies: two complementary strategies for the selective activation of immune cells at the tumor site

Abstract

The activation of the immune system for a selective removal of tumor cells represents an attractive strategy for the treatment of metastatic malignancies, which cannot be cured by existing methodologies. In this review, we examine the design and therapeutic potential of immunocytokines and bispecific antibodies, two classes of bifunctional products which can selectively activate the immune system at the tumor site. Certain protein engineering aspects, such as the choice of the antibody format, are common to both classes of therapeutic agents and can have a profound impact on tumor homing performance in vivo of individual products. However, immunocytokines and bispecific antibodies display different mechanisms of action. Future research activities will reveal whether an additive of even synergistic benefit can be obtained from the judicious combination of these two types of biopharmaceutical agents.

Keywords: antibody engineering; armed antibodies; bispecific antibodies; immunocytokines; immunotherapy of cancer.

Fig. 1. Overview of common formats for immunocytokines.

a) IgG format, cytokine fused to the light chain, b) IgG format, cytokine fused to the heavy chain, c) Diabody, d) bivalent scFv format, here in fusion with heterodimeric cytokine IL12, e) trivalent scFv format, here in fusion with trimeric cytokine TNF, f) SIP format. Constant regions indicated in grey, VH indicated in dark blue, VL indicated in light blue, cytokines indicated in green (circle: monomeric cytokine like e.g. IL2, circle connected to half-circle: heterodimeric cytokine like e.g. IL12, hexagon: homotrimeric cytokine like e.g. TNF).

Fig. 2. Overview of common formats for bispecifc antibodies.

a) knobs-into-hole bispecific antibody, like it is used in the Duobody™ format, b) globular domain proteins fused to IgGs, e.g. FynomAbs™, c) double-variable-domains Immunoglobulins (DVD-IgGs™), d) Bispecific T Cell Engager (BiTE™), e) single-chain diabody (scDb), f) Tribody, g) DART™, h) chemical cross-linking of two Fab fragments, i) TandAb™. Constant regions indicated in grey, VH1 indicated in dark blue, VL1 in light blue, VH2 in dark green and VL2 in light green. Globular domain proteins indicated as dark green hexagons.

Fig. 3. Overview of commonly used scFv-based antibody fragments.

a) Shorter linkers force two scFv fragments to homo- or heterodimerize, resulting in a diabody fragment b) chain order and linker length variations lead to a great diversity of different bispecific antibody fragments