Agonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Since conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigen, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of the tumor microenvironment and highly elevated in solid tumors, as a broadly tumor selective switch. We generated a novel anti-CD137 switch antibody, STA551, which exerts agonistic activity only in the presence of exATP. STA551 demonstrated potent and broad anti-tumor efficacy against all mouse and human tumors tested and a wide therapeutic window without systemic immune activation in mice. STA551 was well tolerated even at 150 mg/kg/week in cynomolgus monkeys. These results provide a strong rationale for the clinical testing of STA551 against a broad variety of cancers regardless of antigen expression, and for the further application of this novel platform to other targets in cancer therapy.

Deoxynivalenol (DON), a trichothecene mycotoxin found in grains and cereal-based foods worldwide, impairs weight gain in experimental animals but the underlying mechanisms remain undetermined. Oral exposure to DON induces rapid and transient upregulation of proinflammatory cytokine expression in the mouse. The latter are known to induce several suppressors of cytokine signaling (SOCS), some of which impair growth hormone (GH) signaling. We hypothesized that oral exposure to DON will induce SOCS expression in the mouse. Real-time PCR and cytokine bead array revealed that oral gavage with DON rapidly (1 h) induced tumor necrosis factor-alpha and interleukin-6 mRNA and protein expression in several organs and plasma, respectively. Upregulation of mRNAs for four well-characterized SOCS (CIS [cytokine-inducible SH2 domain protein], SOCS1, SOCS2, and SOCS3) was either concurrent with (1 h) or subsequent to cytokine upregulation (2 h). Notably, DON-induced SOCS3 mRNAs in muscle, spleen and liver, with CIS1, SOCS1, and SOCS2 occurring to a lesser extent. Hepatic SOCS3 mRNA was a very sensitive indicator of DON exposure with SOCS3 protein being detectable in the liver well after the onset of cytokine decline (5 h). Furthermore, hepatic SOCS upregulation was associated with about 75% suppression of GH-inducible insulin-like growth factor acid labile subunit. Taken together, DON-induced cytokine upregulation corresponded to increased expression of several SOCS, and was associated with suppression of GH-inducible gene expression in the liver.

We examined T-2 toxin-induced lesions in the bone marrow and splenic red pulp as many as 48 hr after oral inoculation with 10 mg/kg body weight of T-2 toxin in female ICR:CD-1 mice. Histopathologically, the bone marrow and splenic red pulp showed a significant hypocellularity. In the bone marrow, the number of myelocytes significantly decreased due to the loss of immature granulocytes, erythroblasts, and lymphocytes. The nuclei of the remaining cells showing pyknosis or karyorrhexis were positively stained by the TdT-mediated dUTP nick end labeling (TUNEL) method, and these TUNEL-positive cells showed ultrastructural characteristics of apoptosis. With agarose gel electrophoresis, DNA ladders were clearly detected in bone marrow samples. The number of TUNEL-positive cells in splenic red pulp increased earlier than it did in the splenic white pulp. Thus, T-2 toxin induced-lesions in the hematopoietic tissues and in the lymphoid tissues were brought about by apoptosis of component cells. We believe that damage to the hematopoietic microenvironment may also play an indirect role in the induction of apoptosis in the bone marrow.

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