Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3

Abstract

Dysregulation of the chemokine system is implicated in a number of autoimmune and inflammatory diseases, as well as cancer. Modulation of chemokine receptor function is a very promising approach for therapeutic intervention. Despite interest from academic groups and pharmaceutical companies, there are currently few approved medicines targeting chemokine receptors. Monoclonal antibodies (mAbs) and antibody-based molecules have been successfully applied in the clinical therapy of cancer and represent a potential new class of therapeutics targeting chemokine receptors belonging to the class of G protein-coupled receptors (GPCRs). Besides conventional mAbs, single-domain antibodies and antibody scaffolds are also gaining attention as promising therapeutics. In this review, we provide an extensive overview of mAbs, singledomain antibodies, and other antibody fragments targeting CXCR4 and ACKR3, formerly referred to as CXCR7. We discuss their unique properties and advantages over smallmolecule compounds, and also refer to the molecules in preclinical and clinical development. We focus on singledomain antibodies and scaffolds and their utilization in GPCR research. Additionally, structural analysis of antibody binding to CXCR4 is discussed. SIGNIFICANCE STATEMENT Modulating the function of GPCRs, and particularly chemokine receptors, draws high interest. A comprehensive review is provided for monoclonal antibodies, antibody fragments, and variants directed at CXCR4 and ACKR3. Their advantageous functional properties, versatile applications as research tools, and use in the clinic are discussed.

Nanobody: A Small Antibody with Big Implications for Tumor Therapeutic Strategy

“…The preliminary experimental results suggested that the NB1-NB3 nanobody did not affect cell-cycle progression but restrained the excretion of angiogenic factor CXCL1. 74 Therefore, it demonstrated that nanobody is a potential alternative to mAb advancing GPCR targeting under the circumstances that there are still no selective antibodies approved against ACKR3, thus ACKR3 targeting nanobodies are expected to reverse the immunosuppressive cancer microenvironment and use as the new clinic therapeutics or research tools.…”

Targeting CXCR4 in AML and ALL

“…At least four monoclonal antibodies (mAbs) against CXCR4 (Ulocuplumab, LY2624587, PF-06747143, and hz515H7) have been tested in humans and many more antibodies, nanobodies, and other fragments targeting the CXCR4/CXCL12 axis are in pre-clinical development [for review see Bobkov et al ( 107 )]. Compared to small molecule inhibitors and peptide-based antagonists, mAbs exhibit longer blood half-lives (up to several weeks for IgG) and, depending on the IgG subclass, can possess Fc domain-mediated effector functions that facilitate the elimination of target-expressing cells via antibody-dependent cell-mediated toxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and/or complement-dependent cytotoxicity.…”

Kinetic Analysis of the Early Signaling Steps of the Human Chemokine Receptor CXCR4

“…Binding of CXCL12 preferentially results in activation of G i proteins as well as β -arrestin recruitment ( Heuninck et al, 2019 ). The CXCR4/CXCL12 axis is an important therapeutic target for the development of new drugs because of its involvement in several types of cancer ( Guo et al, 2016 ; Adlere et al, 2019 ; Bobkov et al, 2019 ) in addition to the well-proven role of CXCR4 as a human immunodeficiency virus coreceptor ( Tsibris and Kuritzkes, 2007 ). Recently, macrophage migration inhibitory factor (MIF) has also been demonstrated to bind to CXCR4, but the binding mode and downstream consequences observed greatly differ from those of CXCL12.…”