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.

Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes.

TSC1 acts coordinately with TSC2 in a complex to inhibit mTOR, an emerging therapeutic target and known promoter of cell growth and cell cycle progression. Perturbation of the mTOR pathway, through abnormal expression or function of pathway genes, could lead to tumorigenesis. TSC1 and TSC2 expression is reduced in invasive breast cancer as compared with normal mammary epithelium. Because single nucleotide polymorphisms (SNPs) in regulatory genes have been implicated in risk and age at diagnosis of breast cancers, systematic SNP association studies were performed on TSC1 and TSC2 SNPs for their associations with clinical features of breast cancer. TSC1 and TSC2 haplotypes were constructed from genotyping of multiple loci in both genes in healthy volunteers. SNPs were selected for further study using a bioinformatics approach based on SNP associations with drug response in NCI-60 cell lines and evidence of selection bias based on haplotype frequencies. Genotyping for five TSC1 and one TSC2 loci were performed on genomic DNA from 1,137 women with breast cancer. This study found that for TSC1 rs7874234, TT variant carriers had a 9-year later age at diagnosis of estrogen receptor positive (ER+), but not ER-, ductal carcinomas (P = 0.0049). No other SNP locus showed an association with age at diagnosis, nor any other breast cancer phenotype. TSC1 rs7874234 is hypothesized to be functional in ER+ breast cancer because the T allele, but not the C allele, may create an estrogen receptor element (ERE) site, resulting in increased TSC1 transcription and subsequent inhibition of mTOR.