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B7-H3/CD276-specific nanobody T3CL11 enables tumor imaging in murine osteosarcoma and colorectal cancer models
Wei Min Chen1, Srujana Kishore2, Vaibavi Srirangam Ramanujam3
1School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Abstract:
Members of the B7 receptor family regulate immune responses and tumor progression. B7-H3 (CD276) is highly expressed in many solid tumors, where it suppresses immune surveillance and is associated with poor clinical prognosis, making it an attractive diagnostic and therapeutic target. Here, we generated T3CL11, a nanobody specific for the human B7-H3 ectodomain, and report a crystal structure at 2.4-Å resolution of its complex with a single IgV-IgC module of B7-H3. T3CL11 binds the membrane-distal IgV domain on the face opposite the two N-glycosylation sites, with recognition mediated primarily by CDR2 and CDR3. In murine osteosarcoma and colorectal cancer models, T3CL11 enabled tumor imaging and co-localized with the clinically evaluated anti-B7-H3 antibody DS-7300a, confirming specific tumor-surface binding in vivo. These findings establish T3CL11 as a promising candidate for the development of B7-H3-targeted diagnostic imaging and future theranostic applications.
Insights
Researchers developed T3CL11, a nanobody targeting B7-H3 (CD276) on solid tumors. This nanobody shows promise for cancer imaging and potential theranostic applications by binding specifically to tumor cells.
Area of Science:
- Immunology
- Structural Biology
- Oncology
Background:
- B7 receptor family members regulate immune responses and tumor progression.
- B7-H3 (CD276) is highly expressed in solid tumors, suppressing immune surveillance and correlating with poor prognosis.
- B7-H3 is a potential target for cancer diagnostics and therapeutics.
Purpose of the Study:
- To generate and characterize a nanobody, T3CL11, specific for the human B7-H3 ectodomain.
- To determine the crystal structure of the T3CL11-B7-H3 complex.
- To evaluate the in vivo efficacy of T3CL11 for tumor imaging.
Main Methods:
- Generation of a nanobody (T3CL11) against human B7-H3.
- X-ray crystallography to determine the structure of the T3CL11-B7-H3 complex at 2.4-Å resolution.
- In vivo tumor imaging in murine osteosarcoma and colorectal cancer models.
Main Results:
- A crystal structure revealed T3CL11 binds the membrane-distal IgV domain of B7-H3, with recognition mediated by CDR2 and CDR3.
- T3CL11 demonstrated specific binding to tumor surfaces in vivo.
- T3CL11 enabled tumor imaging in preclinical cancer models and co-localized with an anti-B7-H3 antibody.
Conclusions:
- T3CL11 is a novel nanobody with high specificity for human B7-H3.
- The structural insights provide a basis for understanding T3CL11-B7-H3 interactions.
- T3CL11 shows potential as a diagnostic imaging agent for B7-H3-expressing tumors and for theranostic applications.
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