A Radiolabeled Fully Human Antibody to Human Aspartyl (Asparaginyl)β-Hydroxylase Is a Promising Agent for Imaging and Therapy of Metastatic Breast Cancer

Abstract

There is a need for novel effective and safe therapies for metastatic breast cancer based on targeting tumor-specific molecular markers of cancer. Human aspartyl (asparaginyl) b-hydroxylase (HAAH) is a highly conserved enzyme that hydroxylates epidermal growth factor-like domains in transformation-associated proteins and is overexpressed in a variety of cancers, including breast cancer. A fully human monoclonal antibody (mAb) PAN-622 has been developed to HAAH. In this study, they describe the development of PAN-622 mAb as an agent for imaging and radioimmunotherapy of metastatic breast cancer. PAN-622 was conjugated to several ligands such as DOTA, CHXA †, and DTPA to enable subsequent radiolabeling and its immunoreactivity was evaluated by an HAAHspecific enzyme-linked immunosorbent assay and binding to the HAAH-positive cells. As a result, DTPA-PAN-622 was chosen to investigate biodistribution in healthy CD-1 female mice and 4T1 mammary tumor-bearing BALB/c mice. The 111 In-DTPA-pan622 mAb concentrated in the primary tumors and to some degree in lung metastases as shown by SPECT/CT and Cherenkov imaging. A pilot therapy study with 213 Bi-DTPA-PAN-622 demonstrated a significant effect on the primary tumor. The authors concluded that human mAb PAN-622 to HAAH is a promising reagent for development of imaging and possible therapeutic agents for the treatment of metastatic breast cancer.

Recent advances in research on aspartate β-hydroxylase (ASPH) in pancreatic cancer: A brief update

“…Sturla et al [63] showed that SMI MO-I-1100 and MO-I-1151 significantly reduced viability and directional motility of glioblastoma multiforme (GBM) cells, and similar effects were observed in GBM cells using lentivirus-sh-ASPH construct, confirming the role of ASPH in these processes [63]. Revskaya et al indicated that radiolabeled human monoclonal antibody (mAb) PAN-622 targeting ASPH on the surface of cancer cells is a promising approach in imaging and, possibly, treatment of metastatic breast cancer [64]. In addition, antisense oligodeoxynucleotide inhibition of ASPH expression significantly reduced the motility of cholangiocarcinoma cells [65] and small interfering RNAs (siRNAs) targeting the exon 2 of ASPH gene inhibited the expression of ASPH and reduced directional motility in HCC cells [22].…”

Bismuth-213 for Targeted Radionuclide Therapy: From Atom to Bedside

“…Breast cancer [102] Bi-Anti-hCD138 Antibody TAT of 7.4 MBq and 11.1 MBq significantly improved survival (p = 0.0303 and p = 0.0070, respectively), whereas HIPEC and HIPEC + TAT treatments did not significantly ameliorate survival as compared to the control group.…”

Aspartate β-hydroxylase as a target for cancer therapy

“…As ASPH is a type II transmembrane protein, its Cterminus carrying the enzymatic domain is exposed outside cells and can be bound by antibodies that can be used for diagnostic and therapeutic purposes. Development of ASPH-specific antibodies has been described in several articles [101][102][103][104][105]. The human IgG1 PAN-622 recognizes the catalytic domain of ASPH.…”

“…This antibody is not directly cytotoxic for tumor cells but is internalized and can deliver cytotoxic moieties into cells [84]. In the subsequent study with a mouse model of metastatic breast cancer, PAN-622 was used for bioimaging and radioimmunotherapy with promising results [104]. Mouse IgG1 monoclonal antibody binding to the C-terminal ASPH domain mediated ADCC by human NK cells [103].…”