Antibody–cytokine fusion proteins: applications in cancer therapy

Abstract

Background-Antibody-cytokine fusion proteins consist of cytokines fused to an antibody to improve antibody-targeted cancer immunotherapy. These molecules have the capacity to enhance the tumoricidal activity of the antibodies and/or activate a secondary antitumor immune response.Objective-To review the strategies used to develop antibody-cytokine fusion proteins and their in vitro and in vivo properties, including preclinical and clinical studies focusing on IL-2, IL-12 and GM-CSF. Methods-Articles were found by searching databases such as PubMed and Clinical Trials of the US National Institutes of Health.Results/conclusion-Multiple antibody-cytokine fusion proteins have demonstrated significant antitumor activity as direct therapeutics or as adjuvants of cancer vaccines in preclinical studies, paving the way for their clinical evaluation.

GM-CSF–Based Fusion Cytokines as Ligands for Immune Modulation

“…One strategy has been to force a fusion to localize to tumors (6)(7)(8). The use of Ab-cytokine fusions is another approach, but like with vaccine approaches, it is limited by the Ags to target.…”

“…For example, IL-3 has a halflife in the range of 5-15 min, the duration of which was extended to several hours by combining it with an anti-IL-3 Ab (5). Similarly, IL-2, IL-12, and GM-CSF have been fused with Abs specific for different cell surface markers, such as Her2, to force the cytokines to localize to the site of the tumor (6). In murine studies, doing so significantly increased the effectiveness of the Abs at reducing the rate of tumor growth in different tumor models.…”

Dual targeting strategies with bispecific antibodies

“…Targeted delivery of these cytokines, e.g., by fusion to an antibody fragment, can result in enhanced therapeutic efficacy by increased tumor localization. 130 Examples include antibodies and antibody fragments fused to IL-2, IL-10, IL-12, IL-15, IFNα, IFNβ, IFNγ, TNF, TRAIL and FasL. Several of these fusion proteins have already entered clinical Phase 1 studies.…”

Advances and Prospects in Cancer Immunotherapy

“…The specific targeting of antibodies fused with cytokines may cause high cytokine concentration in the tumor microenvironment. Therefore, these fusion proteins have the enhanced tumoricidal activity [106] and may activate a secondary antitumor immune response [107].…”