GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors

Abstract

Resistance to immune checkpoint inhibitors (ICI) and other anticancer therapies is often associated with the accumulation of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Therefore, targeting MDSC recruitment or function is of significant interest as a strategy to treat patients with ICI-resistant cancer. The migration and recruitment of MDSCs to the TME is mediated in part by the CD11b/CD18 integrin heterodimer (Mac-1; α_Mβ₂), expressed on both MDSCs and TAMs. However, inhibition or blockade of CD11b/CD18 has had limited success in clinical trials to date, likely since saturation of CD11b requires doses that are not clinically tolerable with the agents tested so far. Interestingly, activation of CD11b with leukadherin-1 was found to reduce macrophage and neutrophil migration in animal models of inflammatory conditions. Preclinical studies with GB1275, a salt form of leukadherin-1, demonstrated that activation of CD11b improves the antitumor immune response and enhances the response to immunotherapy in mouse models of pancreatic adenocarcinoma, breast cancer and lung cancer. Based on the promising results from preclinical studies, a phase 1/2 clinical study (NCT04060342) of GB1275 in patients with advanced solid tumor types known to be resistant or less likely responsive to immuno-oncology therapies, including pancreatic, breast, prostate, and microsatellite-stable colorectal cancer, is ongoing. In this review, we examine targeting MDSCs as a therapeutic approach in cancer therapy, with a special focus on GB1275 preclinical studies laying the rationale for the phase 1/2 clinical study.

Keywords: drug evaluation; investigational; myeloid-derived suppressor cells; preclinical; therapies; translational medical research; tumor microenvironment.

Figure 1

Proposed mechanism of action for GB1275. (A) Inactive CD11b/CD18 integrin heterodimer expressed in circulating leukocytes. (B) GB1275 binding to the allosteric pocket in the α-A-domain of CD11b stabilizes CD11b in the active conformation that is required for ligand binding. (C) On exposure to ligand, GB1275-bound CD11b displays a lower threshold for activation, thereby promoting CD11b-mediated cell adhesion and reduced myeloid cell migration.

Figure 2

Proposed impact of GB1275 on the tumor microenvironment (TME). (A) Tumor-associated macrophages (TAMs) and monocytic myeloid-derived suppressor cells (mMDSCs) suppress T cells in the TME. (B) GB1275 binds CD11b on TAMs and MDSCs, leading to reduced expression of immunosuppressive phenotypes and an influx and activation of tumor-attacking T cells. (C) Exhausted T cells in the TME may then be reinvigorated by checkpoint inhibitor (CPI) therapy. GB1275 combined with a CPI is expected to support effective antitumor immunity. CAF, cancer-associated fibroblast; DC, dendritic cell; PMN-MDSC, polymorphonuclear MDSC.

Figure 3

CD11b expression profile in solid tumors. (A) Relative Itgam (CD11b) mRNA expression across solid tumors from select indications in TCGA PanCancer Atlas (www.cbioportal.org). (B) Quantification of CD11b positive cell prevalence at three different cut-offs (>10%, >25%, or >50% positive) in representative sections from PDAC, CRC, and gastric cancer (n=10/indication). Representative images of CD11b positive infiltrates in PDAC (C), CRC (D) and gastric cancer (E). CRC, colorectal cancer; mRNA, messenger RNA; PDAC, pancreatic ductal adenocarcinoma; TCGA, The Cancer Genome Atlas.