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Publication Abstract from PubMed

BACKGROUND: Targeting the TGF-beta pathway in tumor therapy has proven challenging due to the highly context-dependent functions of TGF-beta. Integrin alphavbeta8, a pivotal activator of TGF-beta, has been implicated in TGF-beta signaling within tumors, as demonstrated by the significant anti-tumor effects of anti-alphavbeta8 antibodies. Nevertheless, the expression profile of alphavbeta8 remains a subject of debate, and the precise mechanisms underlying the anti-tumor effects of anti-alphavbeta8 antibodies are not yet fully elucidated. METHODS: We utilized single-cell RNA sequencing to assess alphavbeta8 expression across various human tumors. An anti-alphavbeta8 antibody was developed and characterized for its binding and blocking properties in vitro. Cryo-EM single-particle analysis was employed to study the detailed interaction between alphavbeta8 and the antibody Fab fragment. The anti-tumor efficacy of the antibody was evaluated in syngeneic mouse models with varying levels of alphavbeta8 expression, both as a monotherapy and in combination with PD-1 antibodies. Human PBMCs were isolated to investigate alphavbeta8 expression in myeloid cells, and macrophages were exposed to the antibody to study its impact on macrophage polarization. Pharmacokinetic studies of the alphavbeta8 antibody were conducted in cynomolgus monkeys. RESULTS: Integrin alphavbeta8 is notably expressed in certain tumor types and tumor-infiltrating macrophages. The specific alphavbeta8 antibody 130H2 demonstrated high affinity, specificity, and blocking potency in vitro. Cryo-EM analysis further revealed that 130H2 interacts exclusively with the beta8 subunit, without binding to the alphav subunit. In vivo studies showed that this antibody significantly inhibited tumor growth and alleviated immunosuppression by promoting immune cell infiltration. Furthermore, combining the antibody with PD-1 inhibition produced a synergistic anti-tumor effect. In human PBMCs, monocytes exhibited high alphavbeta8 expression, and the antibody directly modulated macrophage polarization. Tumors with elevated alphavbeta8 expression were particularly responsive to 130H2 treatment. Additionally, favorable pharmacokinetic properties were observed in cynomolgus monkeys. CONCLUSIONS: In summary, integrin alphavbeta8 is highly expressed in certain tumors and tumor-infiltrating macrophages. Targeting alphavbeta8 with a blocking antibody significantly inhibits tumor growth by modulating macrophage polarization and enhancing immune cell infiltration. Combining alphavbeta8 targeting with PD-1 treatment markedly increases the sensitivity of immune-excluded tumors. These results support further clinical evaluation of alphavbeta8 antibodies.

Specifically blocking alphavbeta8-mediated TGF-beta signaling to reverse immunosuppression by modulating macrophage polarization.,Guo C, Sun H, Du Y, Dai X, Pang Y, Han Z, Xiong X, Li S, Zhang J, Zheng Q, Gui X J Exp Clin Cancer Res. 2025 Jan 2;44(1):1. doi: 10.1186/s13046-024-03250-1. PMID:39743547^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.