Antibody-Cytokine Fusion Proteins for Treatment of Cancer: Engineering Cytokines for Improved Efficacy and Safety

Abstract

The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing IL-2, IL-12, IL-21, TNFα, and interferons α, β and γ have been constructed and have shown anti-tumor activity in pre-clinical and early phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody-cytokine fusion protein, focusing on previously developed constructs and their clinical trial results.

The immunogenicity and anti-tumor effects of a lung cancer DNA vaccine harboring a MUC-1 and GM-CSF fusion gene

“…It has been demonstrated that many cytokines alone have some anti-tumor effect (e.g. GM-CSF, IL-12 and IL-2), and some recombinant cytokines have been developed into an adjuvant in tumor treatments [11,12]. Among these cytokines, GM-CSF is one of the better-studied molecules and has many roles in immune regulation.…”

Intratumorally Establishing Type 2 Innate Lymphoid Cells Blocks Tumor Growth

“…Tumors were removed surgically, cut into 1-to 2-mm 3 pieces, and digested with 5-10 ml DMEM containing collagenase I (1 mg/ml) and DNase I (0.5 mg/ml, Sigma-Aldrich) in a shaking incubator at 37˚C for 1 h. The digested tumor tissues were passed through a 40-mm cell strainer to obtain a single-cell suspension. Whole tumor cells were isolated using Ficoll density-gradient centrifugation.…”

“…C ytokines have the ability to recognize and destroy cancer cells directly or indirectly by regulating the immune system and have been developed as cancer treatments (1)(2)(3). Most cytokines approved as drugs for patients with cancer include the Th1 cytokines (IL-2, IFN-g, TNF-a, and GM-CSF) and other IFN family members (IFN-a and IFN-b) with various proinflammatory cytokines that are in clinical trials (IL-7, IL-12, IL-15, IL-18, and IL-23).…”

Human Antibody Fusion Proteins/Antibody Drug Conjugates in Breast and Ovarian Cancer

“…In ADCs, non-cleavable linkers or chemically labile linkers, including acid-cleavable linkers and reducible linkers, help conjugate antibody to drug [29,30,31]. Due to the chemical method of conjugation, most of these ADCs exist as heterogeneous mixtures, which can result in a narrow therapeutic window and have major pharmacokinetic implications [32].…”

“…Linkers are designed to break inside the cancer cells when exposed to a specific pH or a proteasome [34,35]. In fusion proteins, the goal is to guide the ligand specifically to tumor sites using the mAb linked to a protein moiety [29]. The variable regions (Fv) of antibodies or single-chain variable fragments (scFvs) are generally genetically fused to the protein moiety.…”