Our findings characterize CD276 as promising target and preclinically document the therapeutic potential of CC-3 for BC treatment, providing a strong rationale for evaluation of CC-3 in BC patients in a clinical trial for which the recruitment has recently started.

XmAb808 as monotherapy and in combination with an anti-PD1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen-targeted anti-CD3 (Signal 1) T-cell engagers.

P2, N=55, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

Enoblituzumab, an immunotherapeutic agent targeting CD276, shows both safety and efficacy in activating T cells and oligodendrocyte-like cells against various cancers...Further investigations demonstrate that inhibiting ITGB6 restores sensitivity to PD1 antibodies in mice resistant to anti-PD1 treatment. In summary, our research reveals a resistance mechanism associated with immune checkpoint inhibitor therapy and identifies potential targets to overcome resistance in cancer treatment.

P1, N=40, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial primary completion date: Dec 2025 --> Dec 2029

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2024 --> Dec 2024

Furthermore, NUTM2A-AS1 expression in cisplatin-resistant NB cells was transactivated by NR1D1. In summary, our results unveil the molecular or biological relationship within the NR1D1/NUTM2A-AS1/B7-H3 axis in NB cells under cisplatin treatment, providing an intriguing avenue for fundamental research into cisplatin-resistant NB.

Finally, CC-3 induced potent target cell lysis in a target cell restricted manner. Based on these results, a clinical trial evaluating CC-3 in soft tissue sarcoma is currently in preparation.

P2, N=0, Withdrawn, TJ Biopharma Co., Ltd. | N=160 --> 0 | Trial completion date: Dec 2024 --> Dec 2023 | Suspended --> Withdrawn | Trial primary completion date: Jun 2024 --> Dec 2023

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Sep 2023 --> Jun 2024

Clinical trial results will be published in peer-reviewed journals. Trial registration numbers: ClinicalTrials.cov Registry (NCT05999396) and EU ClinicalTrials Registry (EU trial number 2022-503084-15-00).

P1, N=89, Recruiting, German Cancer Research Center | Not yet recruiting --> Recruiting

P2, N=219, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

B7-H3 may stabilize EGFR to activate its downstream pathway for cancer cell proliferation and resistance to oxaliplatin (OXP)...Overall, these results showed that B7-H3 exhibited a high prevalence in COAD patients and was significantly associated with worse prognosis in COAD patients. Dual targeting of B7-H3 and EGFR signaling might be a potential therapeutic strategy for high-risk COAD patients.

P2/3, N=52, Terminated, Y-mAbs Therapeutics | Trial completion date: Dec 2026 --> Jun 2023 | Active, not recruiting --> Terminated | Trial primary completion date: May 2026 --> Jun 2023; Corporate business decision. Not due to safety or efficacy concerns.

Particularly promising treatments are enoblituzumab for prostate cancer, 131I-omburtamab for central nervous system malignancies, and HS-20093 for small-cell lung cancer but further studies are warranted. These data will be telling of the efficacy of B7-H3 inhibitors in both hematologic and solid malignancies. This study aimed to compile available results of B7-H3 inhibitors in oncology clinical trials.

Alternatives to mutagenic therapies for brain tumors should be explored for patients with CPS. LITT paired with imaging surveillance is a logical strategy to ensure durable outcomes and mitigate treatment-related secondary neoplasms.

P2, N=62, Active, not recruiting, Pediatric Brain Tumor Consortium | Trial completion date: Oct 2029 --> Oct 2030 | Trial primary completion date: Oct 2028 --> Oct 2029

P1, N=220, Recruiting, Xencor, Inc.

P1, N=177, Terminated, Y-mAbs Therapeutics | N=120 --> 177 | Active, not recruiting --> Terminated; Corporate business decision. No safety or efficacy concerns.

P1/2, N=128, Recruiting, Innovent Biologics (Suzhou) Co. Ltd. | Phase classification: P1 --> P1/2

P1, N=54, Terminated, Y-mAbs Therapeutics | Active, not recruiting --> Terminated; Corporate business decision. Not due to safety or efficacy concerns

P1, N=128, Recruiting, Innovent Biologics (Suzhou) Co. Ltd. | Not yet recruiting --> Recruiting

Comprehensive in vitro characterization revealed that targeting the membrane-proximal epitope Q179 of the B7-H3 molecule allowed for a 100-fold reduction of CD3 affinity in our lead compound CC-3 with preserved superior tumor cell killing, efficient T cell activation, proliferation and memory formation, whereas undesired cytokine release was reduced...The trial will consist of a dose escalation part with an accelerated and a standard titration phase to determine the maximum tolerated dose followed by a dose expansion part to define the recommended phase II dose and collect first signs of efficacy. Together, we report on the straight forward development of a novel optimized bsAb from bench to first clinical evaluation that holds promise to improve treatment of CRC patients.

Conclusions HK056–001, a B7H3×4–1BB bsAb with human IgG1 Fc fragment prevents tumor development by killing tumor cells directly via effector functions mediated by NK and cytotoxic T cells. These results indicate that this bsAb holds the potential to be developed as a novel clinical therapy for cancer types with B7H3 expression.

Exploratory objectives include analysis of intratumoral and peripheral PD, including markers of T-cell activation; expression of tumor/immune markers; ctDNA levels; and association of PK and/or PD with clinical outcome. Enrollment has begun.

P2, N=219, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

P1, N=89, Not yet recruiting, German Cancer Research Center

P1, N=0, Withdrawn, Y-mAbs Therapeutics | N=36 --> 0 | Not yet recruiting --> Withdrawn

In an NPC xenograft mouse model with adoptive transfer of primary NK cells, deletion of B7-H3 on tumor cells in combination with anti-PD-L1 treatment restored NK cell-mediated antitumor activity and significantly improved the antitumor efficacy of NK cells. Based on our findings, we conclude that EBV infection can inhibit NK cell-mediated antitumor function by inducing upregulation of B7-H3 expression and provide a rationale for NK cell-based immunotherapies in combination of PD-L1 blockade and overcoming the immunosuppression of B7-H3 to treat EBV-associated NPC.

P1, N=128, Not yet recruiting, Innovent Biologics (Suzhou) Co. Ltd.

Epitope mapping revealed non-overlapping B7-H3 binding epitopes of 6B5 and Enoblituzumab. Taken together, these data suggest that 6B5 is a promising therapeutic anti-human B7-H3 IgG monoclonal antibody that may find clinical application in a range of cancers, including current refractory types.

In pan-human cancers, a high cytotoxic CD38CD39CD4 T-cell gene signature correlates with better clinical prognosis. These results show that mTORC1-hyperactivity, present in many human tumors including tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), drives B7-H3 expression leading to suppression of cytotoxic CD4 T cells.

P1, N=54, Active, not recruiting, Y-mAbs Therapeutics | Trial completion date: Sep 2022 --> Sep 2023

P2, N=160, Suspended, I-Mab Biopharma Co. Ltd. | Initiation date: Dec 2022 --> Dec 2023 | Not yet recruiting --> Suspended

Additionally, in vitro experiments showed that knockdown of CD276 inhibited the proliferation of ovarian cancer (OV) and cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) cell lines. CD276 is a potent biomarker for predicting the prognosis and immunological features in some tumors, and it may play a critical role in the tumor immune microenvironment (TIME) through macrophage-associated signaling.

P2, N=62, Active, not recruiting, Pediatric Brain Tumor Consortium | Trial completion date: Jul 2030 --> Oct 2029 | Trial primary completion date: Jul 2027 --> Oct 2028

In addition to its role in immune modulation, B7-H3 also promotes pro-tumorigenic functions such as tumor migration, invasion, metastases, resistance, and metabolism. In this review, we will provide an overview of this newly characterized immune checkpoint molecule and its development in the management of metastatic NSCLC.

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Sep 2022 --> Jul 2023

B7-H3 TriKE may be particularly useful for patients with bone lesions or as consolidative therapy. Commercial manufacturing of B7-H3 TriKE (GTB-5550) has begun, and a phase I trial is expected in late 2023.