RecombiMAb anti-mouse CD25 (IL-2Rα)

Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies.

Glioblastoma is invariably lethal and responds poorly to immune checkpoint blockade. Here, we examined the impact of regulatory T (Treg) cell depletion on glioblastoma progression and immunotherapy responsiveness. In human glioblastoma, elevated Treg cell signatures correlated with poorer survival outcomes, with these cells expressing high levels of CD25. In Nf1^-/-Pten^-/-EGFRvIII⁺ glioblastoma-bearing mice, a single dose of non-interleukin-2 (IL-2) blocking (NIB) anti-CD25 (anti-CD25^NIB) antibody depleted Treg cells and promoted CD8⁺ T cell clonal expansion and partial tumor control, further enhanced by programmed cell death-1 (PD1)-blockade. Treg cell depletion induced interferon-γ (IFN-γ)-dependent tumor microenvironment remodeling, increasing Fcγ receptor (FcγR) expression on intratumoral myeloid cells and enhancing phagocytosis. Combination of anti-CD25^NIB with anti-EGFRvIII tumor-targeting antibodies resulted in complete tumor control. Anti-human CD25^NIB treatment of glioblastoma patient-derived tumor fragments effectively depleted Treg cells and activated CD8⁺ T cells. These findings underscore the therapeutic relevance of Treg targeting in glioblastoma and unveil potent combination strategies for anti-CD25^NIB based on innate cell activation.

Regulatory T cells (Treg) impede effective antitumor immunity. However, the role of Tregs in the clinical outcomes of patients with triple-negative breast cancer (TNBC) remains controversial. Here, we found that an immunosuppressive TNBC microenvironment is marked by an imbalance between effector αβCD8+ T cells and Tregs harboring hallmarks of highly suppressive effector Tregs (eTreg). Intratumoral eTregs strongly expressed PD-1 and persisted in patients with TNBC resistant to PD-1 blockade. Importantly, CD25 was the most selective surface marker of eTregs in primary TNBC and metastases compared with other candidate targets for eTreg depletion currently being evaluated in trials for patients with advanced TNBC. In a syngeneic TNBC model, the use of Fc-optimized, IL2 sparing, anti-CD25 antibodies synergized with PD-1 blockade to promote systemic antitumor immunity and durable tumor growth control by increasing effector αβCD8+ T-cell/Treg ratios in tumors and in the periphery. Together, this study provides the rationale for the clinical translation of anti-CD25 therapy to improve PD-1 blockade responses in patients with TNBC. Significance: An imbalance between effector CD8+ T cells and CD25high effector Tregs marks immunosuppressive microenvironments in αPD-1-resistant TNBC and can be reversed through effector Treg depletion to increase αPD-1 efficacy.

The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8⁺ T cells with reduced immunosuppressive regulatory T (T_reg) cells, while late MYC acquisition in slow progressors was associated with lower CD8⁺ T cell infiltration and more abundant T_reg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8⁺ T cells versus T_reg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8⁺ T/T_reg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8⁺ T cell cytotoxicity or depleting T_reg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.