RESUMEN
Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs.
Asunto(s)
Inmunidad Innata , Inmunoconjugados , Interferones , Proteínas de la Membrana , Animales , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/inmunología , Inmunidad Innata/efectos de los fármacos , Femenino , Humanos , Ratones , Línea Celular Tumoral , Inmunoconjugados/farmacología , Inmunoconjugados/administración & dosificación , Interferones/metabolismo , Interferón lambda , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Interferón Tipo I/inmunología , Citocinas/metabolismo , Células Mieloides/inmunología , Células Mieloides/efectos de los fármacos , Inmunoterapia/métodos , Ratones Endogámicos C57BL , Receptores de IgG/agonistas , Receptores de IgG/metabolismo , Receptores de IgG/inmunologíaRESUMEN
Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.