SAR445877: A PD-1-targeted IL-15 mutein selectively activates PD-1+ T cells resulting in therapeutic activity across pre-clinical mouse models and in early human clinical trials

Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses due to insufficient T cell reinvigoration. Cytokines offer promise for enhancing immunotherapy, but their clinical use is limited by toxicity and a narrow therapeutic index. Immunocytokines-engineered fusion proteins combining antibody specificity with cytokine activity-aim to overcome these challenges by targeting cytokine delivery to immune cells or the tumor microenvironment. Here, we describe SAR445877 (SAR'877), a novel PD-1-targeted immunocytokine that fuses a high-affinity anti-PD-1 antibody with a detuned IL-15/IL-15Ralpha sushi domain complex. SAR'877 blocks PD-1/PD-L1 and PD-1/PD-L2 interactions while selectively delivering IL-15 signals to PD-1⁺ T cells, enhancing proliferation and activation of antigen-experienced CD8⁺ and CD4⁺ T cells and NK cells, while minimizing systemic inflammation. Mechanistically, SAR'877 activates STAT5 signaling in PD-1⁺ lymphocytes and restores effector function in exhausted T cells. In preclinical models, a murine surrogate of SAR'877 accelerated viral clearance and induced robust anti-tumor immunity by expanding cytotoxic CD8⁺ T cells and promoting Th1 polarization. Notably, SAR'877 outperformed anti-PD-1 plus untargeted IL-15, highlighting the therapeutic potential of targeted IL-15 delivery. SAR'877 is being tested clinically in an open-label, multicenter, phase 1/2 study in adults with any type of measurable, advanced unresectable or metastatic solid tumor (NCT05584670). In part 1, SAR445877 was administered intravenously at two dosing schedules (Q2W and QW). Patients with advanced solid tumors that do not typically respond or were resistant/refractory to immune checkpoint inhibitors (ICI), and with at least 1 measurable lesion per RECIST 1.1, were eligible. Confirmed partial response was reported in 5 pts (Q2W) and in 2 pts (QW) bearing melanoma, CRC, SCC of the scalp, penile cancer, adnexal carcinoma, urothelial carcinoma, and myxofibrosarcoma, with benefits lasting > 1 year (ASCO 2025). Five of the 7 pts had progressed on prior immunotherapy. SAR'877 monotherapy demonstrated a tolerable safety profile and promising antitumor activity in patients with advanced solid tumors unresponsive or resistant to ICI.