Aminopeptidase N (CD13): Expression, Prognostic Impact, and Use as Therapeutic Target for Tissue Factor Induced Tumor Vascular Infarction in Soft Tissue Sarcoma

Abstract

Aminopeptidase N (CD13) is expressed on tumor vasculature and tumor cells. It represents a candidate for targeted therapy, e.g., by truncated tissue factor (tTF)-NGR, binding to CD13, and causing tumor vascular thrombosis. We analyzed CD13 expression by immunohistochemistry in 97 patients with STS who were treated by wide resection and uniform chemo-radio-chemotherapy. Using a semiquantitative score with four intensity levels, CD13 was expressed by tumor vasculature, or tumor cells, or both (composite value, intensity scores 1-3) in 93.9% of the STS. In 49.5% tumor cells, in 48.5% vascular/perivascular cells, and in 58.8%, composite value showed strong intensity score 3 staining. Leiomyosarcoma and synovial sarcoma showed low expression; fibrosarcoma and undifferentiated pleomorphic sarcoma showed high expression. We found a significant prognostic impact of CD13, as high expression in tumor cells or vascular/perivascular cells correlated with better relapse-free survival and overall survival. CD13 retained prognostic significance in multivariable analyses. Systemic tTF-NGR resulted in significant growth reduction of CD13-positive human HT1080 sarcoma cell line xenografts. Our results recommend further investigation of tTF-NGR in STS patients. CD13 might be a suitable predictive biomarker for patient selection.

CD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110

“…Indeed, there is a very active research on tumor stratification based on CD13 expression, and there are many reports in the literature indicating that CD13 expression is an unfavorable prognosis factor in a variety of cancers. Those tumors include pancreas [10] and colon cancers [11], non-small cell lung cancer [12,13], malignant pleural mesothelioma [14], hepatoblastoma [15], hepatocellular carcinoma [35], clear cell papillary renal cell carcinoma [36], scirrhous gastric cancer [37], lymphoplasmatic lymphoma [38], and soft tissue sarcoma [16]. Some of these tumors are rare and/or have poor prognosis, and new therapeutic approaches are urgently needed to increase patient's survival.…”

“…In addition, there is evidence showing a critical role of CD13-positive bone marrow-derived myeloid cells in supporting tumor growth, angiogenesis, and metastasis [8], thus highlighting CD13 as a potential antitumor target [9]. Besides, high expression of CD13 in cancer cells is associated with bad prognosis and poor patient survival in pancreas [10] and colon cancers [11], non-small cell lung cancer [12,13], malignant pleural mesothelioma [14], hepatoblastoma [15], and soft tissue sarcoma [16] among others. In addition, CD13 has been shown to be a target for myeloid malignancies [17].…”

First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study

“…Median age of these patients was 54 years (range 19-74), with 4 being female. We treated patients with various malignant tumor entities during dose escalation and enriched for sarcoma patients within the verification cohorts, since soft tissue sarcomas (STS) have high CD13 target expression [20]. Figure 1 depicts the dose levels and cycles for all patients treated with tTF-NGR ( Figure 1, see also Table 1).…”

“…Interestingly, we have observed major tumor blood flow reductions in MRI as measured by k-trans and VVF also in patients with CD13 positivity (intensity scores 2; for methodology see ref. 20) of the tumor vasculature only, with the tumor cells being CD13-negative (Supplementary Figure S3).…”

“…We have designed and studied a new class of fusion proteins carrying NGR peptides instead of the transmembrane domain at the C-terminus of truncated tissue factor (tTF) to induce tumor vascular thrombosis and occlusion with subsequent infarction [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. These fusion proteins were tested in vitro and in vivo for essential therapeutic properties, such as pro-coagulatory activity, specific binding to their respective target molecules on stimulated endothelial cells (EC) or pericytes, in vivo intratumoral accumulation, in vivo intratumoral activation of coagulation, tumor vascular occlusion and inhibition of blood flow, pharmacodynamic properties including therapeutic antitumor activity in xenotransplants of human tumors from different histologic origin, and finally rodent as well as non-rodent animal safety and toxicology (Investigator’s Brochure (IB), authors on file) [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. The results of the first-in-class phase I trial of the lead protein tTF-NGR in late-stage cancer patients are presented here.…”