The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization

Abstract

Key Points• NOX-A12, a structured mirrorimage RNA oligonucleotide that neutralizes CXCL12, interferes with CLL migration and drug resistance.• NOX-A12 inhibits chemotaxis and sensitizes CLL cells toward cytotoxic drugs, providing a rationale for NOX-A12 combination therapy.The CXC chemokine ligand (CXCL12, or stromal cell-derived factor-1 as previously known) plays a critical role for homing and retention of chronic lymphocytic leukemia (CLL) cells in tissues such as the bone marrow (BM). In tissues, stromal cells constitutively secrete and present CXCL12 via cell-surface-bound glycosaminoglycans (GAGs), thereby attracting CLL cells and protecting them from cytotoxic drugs, a mechanism that may account for residual disease after conventional CLL therapy. NOX-A12, an RNA oligonucleotide in L-configuration (Spiegelmer) that binds and neutralizes CXCL12, was developed for interference with CXCL12 in the tumor microenvironment and for cell mobilization. Here, we examined effects of NOX-A12 on CLL cell migration and drug sensitivity. We found that NOX-A12 effectively inhibited CXCL12-induced chemotaxis of CLL cells. In contrast, NOX-A12 increased CLL migration underneath a confluent layer of BM stromal cells (BMSCs) due to interference with the CXCL12 gradient established by BMSCs. In particular, NOX-A12 competes with GAGs such as heparin for CXCL12 binding, leading to the release of CXCL12 from stromal cell-surface-bound GAGs, and thereby to neutralization of the chemokine. Furthermore, NOX-A12 sensitizes CLL cells toward bendamustine and fludarabine in BMSC cocultures. These data demonstrate that NOX-A12 effectively interferes with CLL cell migration and BMSC-mediated drug resistance, and establishes a rationale for clinical development of NOX-A12 in combination with conventional agents in CLL. (Blood.

What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

“…Mogamulizumab, a monoclonal antibody targeting CCR4, recently became the first biologic to be approved for cutaneous T-cell lymphoma (33). In a complementary effort, antibodies (7, 148) and therapeutic nucleotides (35, 53, 95) are pursued as agents targeting chemokines. With all of these agents, oral availability is out of question; however, various approaches to improving metabolic stability have been successful (18, 95).…”

Advances in stem cell mobilization

“…NOX-A12 is currently being studied for its role in sensitizing malignant cells to chemotherapy in chronic lymphocytic leukemia (CLL). 116-118 It’s effect in inhibiting myeloma cell dissemination to distant BM niches in early plasma cell dyscrasias is also being explored. 119 …”

Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade

“…NOX-A12 was previously shown to not only directly bind and inhibit, but also detach the cell-surface bound CXCL12, leading to abrogation of the CXCL12 gradient (10). Of note, NOX-A12 inhibits the interaction of CXCL12 with both its receptors, CXCR4 and CXCR7 (9,11).…”