Antibody to CD137 Activated by Extracellular Adenosine Triphosphate Is Tumor Selective and Broadly Effective In Vivo without Systemic Immune Activation.

Agonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Because conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigens, 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 antitumor 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. SIGNIFICANCE: Reported CD137 agonists suffer from either systemic toxicity or limited efficacy against antigen-specific cancers. STA551, an antibody designed to agonize CD137 only in the presence of extracellular ATP, inhibited tumor growth in a broad variety of cancer models without any systemic toxicity or dependence on antigen expression.See related commentary by Keenan and Fong, p. 20.This article is highlighted in the In This Issue feature, p. 1.

Effects of cadmium exposure on Iberian ribbed newt (Pleurodeles waltl) testes.

To characterize the histomorphologic effects of cadmium on adult newt testes, male Iberian ribbed newts (6 months post-hatching) were intraperitoneally exposed to a single dose of 50 mg/kg of cadmium, with histologic analysis of the testes at 24, 48, 72, and 96 h. Beginning 24 h after cadmium exposure, apoptosis of spermatogonia and spermatocytes was observed, and congestion was observed in the interstitial vessels of the testes. Throughout the experimental period, the rates of pyknotic cells and TUNEL and cleaved caspase-3 positivity were significantly higher in the spermatogonia and spermatocytes of cadmium-treated newts compared with control newts. There were no significant differences between cadmium-treated and control newts in phospho-histone H3 positivity in the spermatogonia and spermatocytes. These results suggest that spermatogonia and spermatocytes in adult Iberian ribbed newts are highly sensitive to cadmium. This is the first report of the histomorphologic characteristics of cadmium-induced testicular dysfunction in newts.

Effects of cadmium exposure on medaka (Oryzias latipes) testes.

Adult male medaka (Oryzias latipes) were exposed to 10 ppm of cadmium for 96 h, and the testes were examined histopathologically. Numerous apoptotic cells were found in the spermatogonia and spermatocytes at 72 and 96 h after initiation of cadmium exposure, and the pyknotic index, TUNEL-positive rate, and cleaved caspase-3-positive rate in the spermatogonia and spermatocytes of the cadmium-treated group were higher compared with the control group. No significant difference between the control and cadmium-treated groups was found in the phospho-histone H3-positive rate in the spermatogonia and spermatocytes. No edematous, hemorrhagic, or necrotic changes were observed within the testes in the cadmium-treated group. These results suggest that spermatogonia and spermatocytes in medaka testes are highly sensitive to cadmium. Exposure to 10 ppm of cadmium induced histopathologic changes in the testes that were similar to those described in rodents exposed to low doses of cadmium.

Cutaneous histiocytic sarcoma with E-cadherin expression in a Pembroke Welsh Corgi dog.

An 11-year-old male neutered Pembroke Welsh Corgi dog displayed a mass measuring 7.5 cm × 6.6 cm × 1.6 cm in the skin. Neoplastic tissue was nonencapsulated, and the neoplastic cells showed infiltrative growth into the surrounding tissue on microscopic examination. The neoplastic tissue was mainly located from the dermis to the subcutis. Epidermotropism of neoplastic cells was not observed. The tissue was composed of irregular, solid nests of round to polygonal cells. Nests were separated by fine fibrovascular stroma. Mitotic index was high (7.90 ± 0.38 per high power field) and extensive necrosis was observed in the neoplastic tissue. Vascular invasion was often observed in the neoplastic tissue. Neoplastic cells were positive for vimentin, HLA-DR antigen, Iba1, CD18, and E-cadherin, but cells did not express cytokeratin, S100, CD20, CD79α, CD3, MUM-1, lambda light chain, kappa light chain, lysozyme, CD204, or CD11d by immunohistochemistry. Electron microscopic analysis revealed dendrites on these cells. From the above-mentioned findings, the tumor was diagnosed as a cutaneous histiocytic sarcoma with E-cadherin expression. It is possible that neoplastic cells in the present case were derived from cutaneous Langerhans cell. To our knowledge, cutaneous histiocytic sarcoma with E-cadherin expression in domestic animals has not been previously diagnosed in domestic animals.