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SHR-2005, an FcγR-Dependent CD40 Agonistic Antibody with Potent Antitumor Activities and Favorable Safety Profile
Published version of a preprint
Abstract
Activation of CD40, a pivotal component of immune oncology, could facilitate the infiltration of immune cells into the tumor microenvironment. In this investigation, we characterized SHR-2005, a second-generation CD40 agonistic mAb, as a potential candidate for cancer immune therapy. Our results showed that SHR-2005 possessed high affinity in binding to both human and rhesus CD40 and could effectively compete with CD40L for CD40 binding. Notably, SHR-2005 was engineered to exert a strong affinity for human FcγRIIb, consistent with its observed Fc receptor–dependent agonistic activity. Treatment with SHR-2005 led to robust activation of the CD40 signaling pathway and subsequent immune response. The murine surrogate SHR-2005–mIgG1 exhibited potent inhibition of tumor growth in the MC38 allograft model and showed enhanced antitumor efficacy in combination with the anti–PD-L1 antibody. Furthermore, intravesical instillation of SHR-2005–mIgG1 also increased the populations of dendritic cells (DC), CD3+ T cells, and CD4+ T cells in bladder tissue. No obvious abnormality except for a reversible local irritation was observed via intravesical instillation. Notably, SHR-2005 induced significantly lower IL-6 secretion than the APX005M analogue in human peripheral blood mononuclear cells, indicating a favorable safety profile. In conclusion, the CD40 agonistic antibody SHR-2005 was highly reliant on FcγR for agonistic activation and exhibited promising potential for clinical development as monotherapy or in combination with the anti–PD-L1 antibody for the treatment of solid tumors. Based on promising efficacy and tolerance in preclinical studies, SHR-2005 is currently being evaluated in an ongoing phase I clinical trial for the intravesical treatment of high-risk non–muscle-invasive bladder cancer.
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Metadata
- Authors
- Wang, L.-M., Yang, C., Sun, X., Tian, Y., Zhang, J., Wang, X., Zhou, L., Wang, Z., Lin, Y., Wu, T., Zhang, W., Li, J., & Liao, C.
- Affiliations
- Jiangsu Hengrui Medicine (China) (CN)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Liao, Cheng
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2025-08-07
- Volume
- 24
- Issue
- 11
- Pages
- 1671-1684
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W4413721082
- Cited by
- 2
- References
- 42
- Citations by year
- 2026: 2
- FWCI
- 0.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Jiangsu Hengrui Medicine (N/A)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- FcγRIIB, CD40 signaling, cancer immunotherapy, anti-PD-L1 combination therapy, intravesical instillation, non-muscle-invasive bladder cancer, tumor microenvironment, dendritic cells, interleukin-6, safety profile
- MeSH terms
- Animals, Antibodies, Monoclonal, Female, Humans, Receptors, IgG, CD40 Antigens, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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