巨噬细胞衔接型 IgG4 抗体触发对整合素 αvβ3⁺ 肿瘤的细胞毒性

Integrin v 3, absent in most normal cells, has emerged as both a marker and a driver of tumor stemness and drug resistance in epithelial cancers, making it an attractive therapeutic target. The humanized IgG1 anti- v 3 antibody etaracizumab was originally developed to exploit NK cell-mediated cytotoxicity against v 3-positive tumors.

However, despite its favorable safety profile and clinical efficacy, its impact was insufficient for further development.

We previously discovered that v 3-positive epithelial tumors exhibit a tumor-associated macrophage (TAM)-rich microenvironment with limited NK-cell infiltration, potentially limiting the effectiveness of etaracizumab. In this study, we hypothesized that re-engineering the anti- v 3 antibody to activate TAM-mediated cytotoxicity would enhance its antitumor activity.

We developed a fully human IgG4 variant of etaracizumab (anti- v 3 G4) with identical affinity for integrin v 3, but optimized for activation of CD64, an immune effector cell-activating receptor, selectively expressed on macrophages. In organotypic cultures of patients with lung cancer and mouse lung cancer xenografts, anti- v 3 G4 demonstrated superior antitumor activity compared with its IgG1 counterpart.

Mechanistically, this enhancement was driven by CD64 activation in TAMs, leading to robust upregulation of inducible nitric oxide synthase, a pivotal enzyme for immune effector-mediated cytotoxicity.

Our findings reveal a powerful strategy for targeting highly aggressive, drug-resistant integrin v 3-positive tumors by harnessing TAMs for antibody-mediated cancer therapy and demonstrate that this Fc switch approach may be broadly applicable to other targets in TAM-enriched tumor microenvironments.