Abstract
High tumor regulatory T (Treg) cell infiltration is associated with poor prognosis of many cancers. CD25 is highly expressed on tumor Treg cells and is a potential target for Treg deletion. Previously characterized anti-CD25 antibodies appear to have limited efficacy in tumor inhibition. Here we identified two human anti-CD25 antibodies, BA9 and BT942, which did not prevent the activation of IL-2R signaling pathway by IL-2. BT942 had weaker binding and cytotoxic activity to human CD25-expressing cell lines than BA9. But both demonstrated significant tumor growth inhibition in early and late-stage animal cancer models. BT942 resulted in a higher expansion of CD8+ T cells and CD4+ T cells in tumor microenvironment in mouse MC38 model compared to BA9. BT942 also demonstrated significant higher tumor growth inhibition and higher expansion of CD8+ T cells and CD4+ T cells in combination with an anti-PD1 antibody. Pharmacokinetic study of BT942 in cynomolgus monkeys demonstrated a half-life of 206.97 ± 19.03 h. Structural analysis by cryo-EM revealed that BT942 recognizes an epitope on opposite side of the CD25-IL-2 binding site, consistent with no IL-2 signaling blockade in vitro. BT942 appears to be an excellent candidate for cancer immunotherapy.
Highlights
High tumor regulatory T (Treg) cell infiltration is associated with poor prognosis of many cancers
Regulatory T (Treg) cell population accounts for only 5% of CD4+ T cells, which are characterized by constitutively high expression of human CD25 and immune s uppression[1,2]
Enriched phages were used to infect E. coli TG1 for expressing single-chain variable fragments and the binding and blocking activity were tested by ELISA
Summary
High tumor regulatory T (Treg) cell infiltration is associated with poor prognosis of many cancers. BT942 had weaker binding and cytotoxic activity to human CD25expressing cell lines than BA9 Both demonstrated significant tumor growth inhibition in early and late-stage animal cancer models. In addition to antibodies targeting CD25, Smyth and colleagues[22] revealed that antibodies against other targets such as CTLA4, OX40 and GITR may facilitate the elimination of regulatory T cells in tumor microenvironment by effector functions of the a ntibody[22,23,24,25] Killing of regulatory T cells may be more important than the antibody-mediated activation of effector T cells for the anti-tumor activities of those antibodies Among those targets, CD25 is expressed at high level[26]
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