Evolution of the magic bullet: Single chain antibody fragments for the targeted delivery of immunomodulatory proteins

Abstract

Immunocytokines are fusion proteins that combine the specific antigen binding capacities of an antibody or derivative thereof and the potent bioactivity of a cytokine partner. These novel biopharmaceuticals have been directed to various targets of oncological as well as non-oncological origin and a handful of promising constructs are currently advancing in the clinical trial pipeline. Several factors such as the choice of a disease specific antigen, the antibody format and the modulatory nature of the payload are crucial, not only for therapeutic efficacy and safety but also for the commercial success of such a product. In this review, we provide an overview of the basic principles and obstacles in immunocytokine design with a specific focus on single chain antibody fragment-based constructs that employ interleukins as the immunoactive component. Impact statement Selective activation of the immune system in a variety of malignancies represents an attractive approach when existing strategies have failed to provide adequate treatment options. Immunocytokines as a novel class of bifunctional protein therapeutics have emerged recently and generated promising results in preclinical and clinical studies. In order to harness their full potential, multiple different aspects have to be taken into consideration. Several key points of these fusion constructs are discussed here and should provide an outline for the development of novel products based on an overview of selected formats.

Keywords: Immunocytokines; cancer; inflammatory diseases; interleukin; single-chain antibody fragment.

Figure 1.

Diagrammatic comparison between the mode of action of immunocytokines based on the monomeric scFv and the homodimeric diabody format. Binding of the targeting moiety to the respective antigen on the target cell enables the recruitment of immune cells via the specific cytokine receptor. Due to their increased valency, diabodies usually exhibit longer retention times at the actual target site. (A color version of this figure is available in the online journal.)

Figure 2.

Comprehensive overview of putative antibody formats and immunocytokines based on the scFv and the homodimeric diabody format. The length of the linker between the V_L and the V_H segment determines if a monovalent scFv (linker size >12 aa) or a divalent diabody (linker size <11 aa) is formed. Depending on the modular arrangement of the cytokine and the targeting moiety, scFv-based immunocytokines can either be monovalent (e.g. MOV19-IL2) or divalent (e.g. F8-IL7-F8) for the respective antigen. The name of a representative immunocytokine is given below every construct. (A color version of this figure is available in the online journal.)