P1/2, N=179, Active, not recruiting, Genmab | Recruiting --> Active, not recruiting | N=400 --> 179

P1, N=110, Recruiting, Zhejiang Kanova Biopharmaceutical Co., LTD | Not yet recruiting --> Recruiting

P1, N=48, Completed, Cullinan Therapeutics Inc. | Recruiting --> Completed | N=108 --> 48 | Trial completion date: Jun 2024 --> Sep 2024

P1/2, N=400, Recruiting, Genmab | Trial completion date: Jun 2026 --> Mar 2027 | Trial primary completion date: Jan 2026 --> Jan 2027

P1/2, N=40, Terminated, NextCure, Inc. | Trial completion date: Oct 2024 --> Jan 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2024 --> Jan 2024; Due to the limited activity in Phase 1, NextCure decided to discontinue development of the anti-B7-H4 antibody monotherapy trial (NC762-01) to move forward with a prioritized B7-H4 ADC program.

P1/2, N=500, Recruiting, Genmab | Trial completion date: Aug 2025 --> Jun 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

P1, N=110, Not yet recruiting, Suzhou Kanova Biopharmaceutical Co., LTD

P1/2, N=40, Active, not recruiting, NextCure, Inc. | Recruiting --> Active, not recruiting | N=170 --> 40

P1, N=96, Recruiting, ABL Bio, Inc.

P1, N=30, Terminated, Pfizer | Trial completion date: Jan 2024 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2024 --> Oct 2023; Pfizer has made an internal business decision to not continue further development of PF-07260437. This decision was not due to major safety concerns or requests from any regulatory authorities.

We found that HR+ breast cancer cell lines treated with the selective estrogen-degrader fulvestrant, displayed increased B7-H4 levels and combination treatment of EVOLVE-106 with fulvestrant increases EC50 of tumor killing by 5–8 fold. Conclusions These data support the potential positioning of EVOLVE-106 as a first-in-category immunotherapeutic approach for patients with Her2 receptor low breast cancers, and both estrogen receptor positive and negative tumors, including TNBC.

Conclusions B7H4 and 4–1BB expression in cancer cells, PBMC and solid tumors, together with robust B7H4-dependent single agent activity of CLN-418 in preclinical tumor models, support the development of CLN-418 in patients with difficult-to-treat solid cancers. A Phase 1 dose-escalation trial of CLN-418 is ongoing (NCT05306444).

P1, N=25, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=100 --> 25 | Trial completion date: Sep 2025 --> Jan 2024 | Trial primary completion date: Sep 2025 --> Jan 2024

P1, N=108, Recruiting, Cullinan Oncology, LLC | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

P1, N=100, Recruiting, Pfizer | Trial completion date: Mar 2025 --> Sep 2025 | Trial primary completion date: Mar 2025 --> Sep 2025

Currently, DuoBody-CD3xB7H4 is being investigated in a first-in-human clinical trial for the treatment of solid tumors known to express B7H4 ( NCT05180474 ), in which the MoA and PD, including biomarkers of response, will be clinically explored. Ethics Approval Animal experiments were performed according to the guidelines of the Institutional Animal Care and Use Committee (IACUC) and in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

Ethics Approval The cancer tissue microarray was purchased from Fanpu Biotech, Inc. The company ensured ethical approval from the patients, and patient consent for publication.

Luciferase reporter and chromatin immunoprecipitation assays revealed that this upregulation of VTCN1 gene expression was induced by the recruitment of AhR to the AhR responsive element in the VTCN1 gene promoter in MCF-7 cells. Taken together, AhR directly regulates VTCN1 gene expression in MCF-7 cells.

The B7-H4 expression level is significantly correlated with the p-PKCδ level and tumor metastasis in CRC samples. B7-H4 expression is upregulated by STAT3 activation via PKCδ and plays roles in PKCδ-induced cancer cell motility and metastasis, suggesting that the PKCδ/STAT3/B7-H4 axis may be a potential therapeutic target for CRC.

Overall, ABL103 has a strong in vitro and vivo anti-tumor activity and good safety profile via B7-H4-dependent 4-1BB activation. This strongly suggests ABL103 is a promising therapeutic agent potentially benefitting patients with B7-H4 overexpression.

P1a/1b, N=95, Completed, Five Prime Therapeutics, Inc. | Active, not recruiting --> Completed | N=278 --> 95 | Trial completion date: Jan 2022 --> May 2021 | Trial primary completion date: Jan 2022 --> May 2021

P1/2, N=220, Recruiting, Genmab

P1, N=100, Recruiting, Pfizer | Not yet recruiting --> Recruiting

P1, N=100, Not yet recruiting, Pfizer

In preclinical models of TNBC, a triple combination of NGI-1, camsirubicin (a non-cardiotoxic doxorubicin analog) and PD-L1 blockade was effective in reducing tumor growth. Collectively, our findings uncover a novel strategy for targeting the immunosuppressive molecule B7-H4.

Furthermore, our data revealed that B7-H4 regulated apoptosis and autophagy through the PI3K signaling pathway in HCC cells. Therefore, these results suggested that B7-H4 plays an important role in HCC progression by affecting cell apoptosis and autophagy.

An in vitro killing assay showed that the cytotoxicity of CD8 T cells was inhibited in B7H4-overexpressing tumor cells. These findings suggest that B7H4 in tumor cells is a negative regulator of CD8 T cell activation, expansion and cytotoxicity, indicating that tumor cell-associated B7H4 might be a target for T cell-based cancer immunotherapy.