GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors
Open accessAbstract
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 M β 2), 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.
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CD11b/CD18 agonists developed in PDAC models have shown promising preclinical data and are being tested in the clinic.
“novel agonists developed in PDAC models to target the CD11b/CD18 receptor present on most tumor-infiltrating myeloid subsets have shown promising pre-clinical data, currently being tested in the clinic181,182”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [181]
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Myeloid Cells as Clinical Biomarkers for Immune Checkpoint Blockade
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“26 27–29 In this review, we examine the therapeutic approach of preventing the accumulation and immunosuppressive activities of MDSCs in the TME, with a special focus on GB1275, an allosteric modulator of CD11b, currently being developed for patients with solid tumors that are relapsed or…”
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“Elevated baseline levels of circulating MDSCs 20–23 and tumor resident TAMs 24 25 associate with advanced clinical stage, metastatic status, and worse treatment outcomes across various indications.”
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“Elevated baseline levels of circulating MDSCs 20–23 and tumor resident TAMs 24 25 associate with advanced clinical stage, metastatic status, and worse treatment outcomes across various indications.”
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CD11b deficiency suppresses intestinal tumor growth by reducing myeloid cell recruitment
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“38 50–53 These preclinical results have led to the investigation of PI3K γ inhibitors in several phase 2 clinical studies (NCT03980041, NCT03795610, NCT03961698), and the results are forthcoming.”
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“59 62 63 Interestingly, stabilizing integrins α 4 β 1 , α L β 2 , and α 4 β 7 in an activated state has been shown to increase cell adhesion and decrease eosin-ophil migration, 64–67 suggesting that stabilizing CD11b/ CD18 in an activated state may have a similar effect on cell adhesion and…”
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Agonist Leukadherin-1 Increases CD11b/CD18-Dependent Adhesion Via Membrane Tethers
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“63 68–71 These findings warranted further investigation of CD11b modulation on MDSC migration and function in the TME.”
Wainberg, Z. A., Piha-Paul, S. A., Luke, J., Kim, E. J., Thompson, J. A., Britten, C. D., Johnson, J. M., Pfanzelter, N., Gordon, M. S., Rasco, D. W., et al. (2018) · doi:10.13140/rg.2.2.28962.53443 · Cited by 37 · see citing works
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“63 68–71 These findings warranted further investigation of CD11b modulation on MDSC migration and function in the TME.”
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Positive Allosteric Modulation of CD11b as a Novel Therapeutic Strategy Against Lung Cancer
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Identification of novel agonists of the integrin CD11b/CD18
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Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
Current and future immunotherapeutic approaches in pancreatic cancer treatment
Farhangnia, P., Khorramdelazad, H., Nickho, H., & Delbandi, A. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01561-6 · Cited by 247 · see citing works
Arginase 1 is a key driver of immune suppression in pancreatic cancer
Menjivar, R. E., Nwosu, Z. C., Du, W., Donahue, K. L., Hong, H. S., Espinoza, C. E., Brown, K. L., Velez-Delgado, A., Yan, W., Lima, F., et al. (2023) · eLife · doi:10.7554/elife.80721 · Cited by 180 · see citing works
Ren, Q., Zhang, P., Lin, H., Feng, Y., Chi, H., Zhang, X., Xia, Z., Cai, H., & Yu, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1201573 · Cited by 85 · see citing works
Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer
Shakiba, M., & Tuveson, D. A. (2025) · Nature Immunology · doi:10.1038/s41590-025-02134-6 · Cited by 75 · see citing works
The tumour microenvironment in pancreatic cancer — new clinical challenges, but more opportunities
Kung, H., Zheng, K., Zimmerman, J. W., & Zheng, L. (2025) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-025-01077-z · Cited by 69 · see citing works
“…ADH-503) was demonstrated to partially activate CD11b, resulting in TAM repolarization and a reduction in immunosuppressive myeloid cell infiltration, improved DC activity and promotion of antitumour T cell cytotoxicity with sensitization to anti-PD-1 antibodies in a mouse model of PDAC 260,261 .”
Functional and Therapeutic Significance of Tumor-Associated Macrophages in Colorectal Cancer
Li, Y., Chen, Z., Han, J., Ma, X., Zheng, X., & Chen, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.781233 · Cited by 54 · see citing works
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Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma
Skorupan, N., Domínguez, M. P., Ricci, S. L., & Alewine, C. (2022) · Cancers · doi:10.3390/cancers14174209 · Cited by 32 · see citing works
“Neither of these activities require target saturating concentrations of drugs, an important boon over a true pharmacologic inhibitor [196].”
BackgroundNano-immunotherapy for lung cancer
Lu, Y., Zeng, T., Zhang, H., Li, Y., Zhu, X., Liu, H., Sun, B., Ji, C., Li, T., Huang, L., et al. (2023) · Nano TransMed · doi:10.26599/ntm.2023.9130018 · Cited by 33 · see citing works
Study on the mechanism of MDSC-platelets and their role in the breast cancer microenvironment
Han, X., Song, X., Xiao, Z., Zhu, G., Gao, R., Ni, B., & Li, J. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1310442 · Cited by 29 · see citing works
Wu, H., Li, J., Yao, R., Liu, J., Su, L., & You, W. (2025) · Theranostics · doi:10.7150/thno.113727 · Cited by 29 · see citing works
“Mechanistically, TAMs express CD11b/CD18 integrin heterodimer (Mac-1; αMβ2), which is one of the essential tools required by MDSCs for their migration and recruitment [122].”
Zhang, X., Liang, Q., Cao, Y., Yang, T., An, M., Liu, Z., Yang, J., & Liu, Y. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02598-y · Cited by 26 · see citing works
“In addition, MDSCs induce tumor angiogenesis and metastasis via upregulating the expression of arginase 1, TGF-β, IL-10, and vascular endothelial growth factor (VEGF) [14, 15].”
BackgroundMultifaceted, unique role of CD11c in leukocyte biology
Hou, L., Koutsogiannaki, S., & Yuki, K. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1556992 · Cited by 26 · see citing works
Combination immunotherapy for pancreatic cancer: challenges and future considerations
Gössling, G. C. D. L., Zhen, D. B., Pillarisetty, V. G., & Chiorean, E. G. (2022) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2022.2120471 · Cited by 18 · see citing works
Local ablation disrupts immune evasion in pancreatic cancer
Musiu, C., Adamo, A., Caligola, S., Agostini, A., Frusteri, C., Lupo, F., Boschi, F., Busato, A., Poffe, O., Anselmi, C., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217327 · Cited by 17 · see citing works
Targeting myeloid cells in pancreatic ductal adenocarcinoma: from primary tumors to liver metastasis
Gong, R., Chen, Y., Chang, D. K.-F., Zhang, H., Liu, Z., & Yu, Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1555036 · Cited by 14 · see citing works
Integrins in Health and Disease—Suitable Targets for Treatment?
Klaus, T., Hieber, C., Bros, M., & Grabbe, S. (2024) · Cells · doi:10.3390/cells13030212 · Cited by 15 · see citing works
“Pharmacological activation of MAC-1 using GB1275 (Leukadherin-1), which binds MAC-1 and activates this β 2 integrin by outside-in signaling [328], yielded pronounced anti-tumor effects in numerous studies [142,329,330].”
MethodXu, M., & Gong, J. (2022) · Journal of Oncology · doi:10.1155/2022/2524649 · Cited by 14 · see citing works
“(e LUAD TME status can be determined by analyzing the relationship between immune cell infiltration and the LUAD gene signature, which was previously thought to be a useful indicator for predicting disease outcomes and immunotherapy response in malignancies [33, 34].”
BackgroundHydrogel-Based Therapeutics for Pancreatic Ductal Adenocarcinoma Treatment
Liu, J., Wu, W., Zhu, Q., & Zhu, H. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15102421 · Cited by 11 · see citing works
Naghdibadi, M., Momeni, M., Yavari, P., Gholaminejad, A., & Roointan, A. (2023) · Kidney & Blood Pressure Research · doi:10.1159/000529861 · Cited by 9 · see citing works
“Other identi fi ed drugs were chemotaxis-targeting molecules, including rovelizumab, which is known as a safe and tolerable anti-CD18/CD11b (ITGB2/ITGAM), and maraviroc that target the CCR5/CCL5 axis [59, 60].”
BackgroundZhu, T., Wu, X., Liao, Y., Yan, Y., Yu, M., Wang, L., & Xia, Q. (2023) · Clinical Cancer Bulletin · doi:10.1007/s44272-023-00005-5 · Cited by 8 · see citing works
“Given these functions, CD11b/CD18 blockade promises to reduce the infiltration of most myeloid subsets into the tumor [134].”
BackgroundCellular collusion: cracking the code of immunosuppression and chemo resistance in PDAC
Musiu, C., Lupo, F., Agostini, A., Lionetto, G., Bevere, M., Paiella, S., Carbone, C., Corbo, V., Ugel, S., & Sanctis, F. D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1341079 · Cited by 9 · see citing works
Roche, V., Sandoval, V., Wolford, C., Senders, Z. J., Kim, J. A., Ribeiro, S. P., Huang, A. Y., Sékaly, R., Lyons, J. L., & Zhang, M. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006205 · Cited by 7 · see citing works
Research trends on immunotherapy for pancreatic cancer: A bibliometric analysis
Niu, J., Jiang, W., Fan, D., Li, X., Zhou, W., & Zhang, H. (2023) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2023.2269794 · Cited by 8 · see citing works
The integrin adhesome and control of anti-tumour immunity
Webb, E. R., Black, A., Barth, N. D., Symeonides, S. N., & Brunton, V. G. (2024) · Biochemical Society Transactions · doi:10.1042/bst20240386 · Cited by 6 · see citing works
Leukadherin-1 inhibits NLRP3 inflammasome by blocking inflammasome assembly
Zhang, Y., Zhang, X., Zhang, N., Yu, S., Zhong, Y., & Zhao, K. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110024 · Cited by 5 · see citing works
Dienstmann, R., Ruíz‐García, E., Alsina, M., Ruíz‐Pace, F., Schooten, T. S. G.-V., Martínez‐Ciarpaglini, C., Fernández-Figueroa, E. A., Herrera‐Goepfert, R., Díaz-Romero, C., Lino-Silva, L. S., et al. (2025) · ESMO Open · doi:10.1016/j.esmoop.2025.104482 · Cited by 4 · see citing works
“34,35 5.”
From Ulcerative Colitis to Metastatic Colorectal Cancer
León-Vega, I. I., Oregon, R., Schnoor, M., & Vadillo, E. (2025) · American Journal Of Pathology · doi:10.1016/j.ajpath.2025.01.004 · Cited by 4 · see citing works
Tang, X., Wang, Y., Li, S., Hu, Y., Fan, J., Chen, Z., Guo, R. H., & He, Q. (2025) · Nano Research · doi:10.26599/nr.2025.94907701 · Cited by 3 · see citing works
Meng, X. M., Zhang, Y., Xu, H., Zhang, Y., He, H., Ma, J., & Zhang, X. (2025) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-025-06315-6 · Cited by 2 · see citing works
“Most studies suggest that MDSCs primarily consist of granulocytic myeloid-derived immunosuppressive cells (Gr-MDSCs) and monocytic myeloid-derived immunosuppressive cells (Mo-MDSCs) (Bronte et al. 2016; DeNardo et al. 2021).”
Wu, P., Chen, L., Yang, J., He, C., Tang, A., & Yang, Y. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1784198 · Cited by 2 · see citing works
“…is being evaluated in a Phase 1/2 trial for treatment-resistant solid tumors, including mCRPC. Preclinical studies indicate that its mechanism involves suppressing the migration of myeloid-derived suppressor cells and TAMs, with potential synergy when combined with checkpoint inhibitors (57).”
Cui, Y., Hou, R., Lv, X., Wang, F., Yu, Z., & Cui, Y. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.771749 · Cited by 2 · see citing works
Immunotherapy for Pancreatic Cancer
Sunami, Y., Rieder, S., Michl, P., & Kleeff, J. H. (2023) · Springer eBooks · doi:10.1007/978-3-030-80962-1_223-1 · Cited by 3 · see citing works
Targeting α4β1 integrin: from cyclic to linear ligands, effects of chemical modifications
Giraldi, V., Maurizio, A. M., Cirillo, M., Magnone, P., Fedele, E., Bedini, A., Baiula, M., & Giacomini, D. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117965 · Cited by 1 · see citing works
Targetable axes of tumor-associated macrophages: An MSF framework for precision immunotherapy
Lu, Z., Xu, M., Tang, J., Wang, X., Li, X., & Li, Q. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189458 · Cited by 1 · see citing works
Immunotherapy for Pancreatic Cancer
Sunami, Y., Rieder, S., Michl, P., & Kleeff, J. H. (2025) · Springer eBooks · doi:10.1007/978-3-032-00769-8_223 · Cited by 1 · see citing works
Driving tumor-associated macrophages to a CXCL9Hi/SPP1Low phenotype eliminates pancreatic cancer
Nguyen, Y. T. M., Pfefferlé, M., Oh, J., Simpson, G. G., Walker, S. A., Noguchi, S., Garris, C. S., Deutsch-Williams, R. J., Wirapati, P., Stefano, F. D., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.102938 · Cited by 1 · see citing works
Wang, Q., Zhang, N., Liu, L., Ma, L., Tan, Y., Liu, X., Wu, J., Chen, G., Li, X., Liang, Y., et al. (2023) · Cellular Oncology · doi:10.1007/s13402-023-00808-7 · Cited by 1 · see citing works
“CD11b could regulate the microenvironment by affecting multiple biological processes, and has been proven to exert a crucial role in the occurrence and progression of AML [10, 11 ].”
BackgroundInfluentialTarbell, E., & Jarvis, J. N. (2025) · Human Genetics and Genomics Advances · doi:10.1016/j.xhgg.2025.100424 · Cited by 1 · see citing works
Wakkad, N. E. (2022) · International Journal of Cancer and Biomedical Research · doi:10.21608/jcbr.2022.110181.1239
“Similarly, preclinical studies with GB1275, a salt form of leukadherin1, showed 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 (DeNardo et al., 2021).”
BackgroundStructure and Function of the Leukocyte Integrin αMβ2
Andersen, G. R., & Emsley, J. (2023) · Biology of extracellular matrix · doi:10.1007/978-3-031-23781-2_11
Targeting Myeloid Determinants of Breast Cancer
Kudo‐Saito, C., & Ozaki, Y. (2024) · Interdisciplinary cancer research · doi:10.1007/16833_2024_210
CD11b suppresses TLR7-driven inflammatory signaling to protect against lupus nephritisPreprint
Li, X., Villanueva, V., Jiménez, V., Nguyen, B., Chauhan, N. R., Khan, S. Q., Dorschner, J. M., Jensen, M. A., Alzahrani, K. A., HuiTing, W., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.26.605143
Intercellular Adhesion Disorders In Tumorigenesis
Bocharova, O. A., Карпова, Р. В., Бочаров, Е. В., Kucheryanu, V. G., Kosorukov, V. S., & Stilidi, I. S. (2024) · Russian Open Medical Journal · doi:10.15275/rusomj.2024.0301
“GB1275, a Mac-1 agonist, improved antitumor immunity, which led to an increase in both the number of tumor-infiltrating CTL and their cytolytic activity in pancreatic ductal adenocarcinoma, as well as breast, prostate, and microsatellite stable colorectal cancer [63].”
BackgroundLeukocyte Integrins: Regulation of Immune Cell Trafficking and Activation
Lowell, C. A. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00237-4
Zhang, X., Liang, Q., Cao, Y., Yang, T., An, M., Liu, Z., Yang, J., & Liu, Y. (2024) · Figshare · doi:10.6084/m9.figshare.25996806
The complement system contributes to the immunosuppressive microenvironment of uveal melanoma
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“Fibroblast interactions with MDSC and macrophages through C3–ITGAM and C3– C3AR pathways may contribute to MDSC recruitment [52, 53], differentiation [54], and macrophages skewing towards M2-like polarization [55, 56].”
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Secreted Cyclophilin A Induces M1 and M2 Macrophage Polarization in the THP-1 Model in vitro
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- Authors
- DeNardo, D. G., Galkin, A., Dupont, J., Zhou, L., & Bendell, J.
- Affiliations
- Washington University in St. Louis (US)
- Gossamer Bio (United States) (US)
- Sarah Cannon (US)
- Corresponding author
- DeNardo, David G
- Venue
- Journal for ImmunoTherapy of Cancer
- Publisher
- BMJ
- Published
- 2021-08
- Volume
- 9
- Issue
- 8
- Pages
- e003005
- ISSN
- 2051-1426 (ISSN-L)
- PMC
- PMC8404448
- OpenAlex
- W3194095242
- Cited by
- 53
- References
- 100
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 11 · 2023: 15 · 2022: 5 · 2021: 1
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-11-01)
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Gossamer Inc in collaboration with Merck & Co, Inc
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD11b/CD18 integrin, myeloid-derived suppressor cells, tumor-associated macrophages, immune checkpoint inhibitor resistance, tumor microenvironment, combination immunotherapy, solid tumors, pancreatic ductal adenocarcinoma, breast cancer, lung cancer, colorectal cancer, prostate cancer, antitumor immunity
- MeSH terms
- Myeloid-Derived Suppressor Cells, Animals, Benzoates, Humans, Immunotherapy, Neoplasms, Thiohydantoins, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, CD11b Antigen, Cell Line, Tumor, Tumor Microenvironment
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