Radioimmunotherapy with an 211At-labeled anti–tissue factor antibody protected by sodium ascorbate

Tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is abundantly expressed in various cancers including gastric cancer. Anti-TF monoclonal antibodies (mAbs) capable of targeting cancers have been successfully applied to armed antibodies such as antibody-drug conjugates (ADCs) and molecular imaging probes. We prepared an anti-TF mAb, clone 1084, labeled with astatine-211 (²¹¹At), as a promising alpha emitter for cancer treatment. Alpha particles are characterized by high linear energy transfer and a range of 50-100 µm in tissue. Therefore, selective and efficient tumor accumulation of alpha emitters results in potent antitumor activities against cancer cells with minor effects on normal cells adjacent to the tumor. Although the ²¹¹At-conjugated clone 1084 (²¹¹At-anti-TF mAb) was disrupted by an ²¹¹At-induced radiochemical reaction, we demonstrated that astatinated anti-TF mAbs eluted in 0.6% or 1.2% sodium ascorbate (SA) solution were protected from antibody denaturation, which contributed to the maintenance of cellular binding activities and cytocidal effects of this immunoconjugate. Although body weight loss was observed in mice administered a 1.2% SA solution, the loss was transient and the radioprotectant seemed to be tolerable in vivo. In a high TF–expressing gastric cancer xenograft model, ²¹¹At-anti-TF mAb in 1.2% SA exerted a significantly greater antitumor effect than nonprotected ²¹¹At-anti-TF mAb. Moreover, the antitumor activities of the protected immunoconjugate in gastric cancer xenograft models were dependent on the level of TF in cancer cells. These findings suggest the clinical availability of the radioprotectant and applicability of clone 1084 to ²¹¹At-radioimmunotherapy.     

Long-term efficacy of immune checkpoint inhibitors in non-small cell lung cancer patients harboring MET exon 14 skipping mutations

International Journal of Clinical Oncology - MET exon 14 skipping mutation, observed in 3–4% of non-small cell lung cancer (NSCLC), is emerging as a targetable alteration. In recent years,...     

Attainment of glycaemic goals by step-up therapy with biphasic insulin aspart-70/30 in Japanese type 2 diabetic patients

We have made step-up titration protocol with biphasic insulin aspart-70/30 (BIAsp 30), and tried to achieve glycemic goals in poorly controlled Japanese type 2 diabetic patients. We summarized all results obtained to analyze the effectiveness of our protocol. The target of glycaemic control was defined as HbA1c over 7.0 %. In our insulin initiation protocol, all patients started a once-daily injection of BIAsp 30 before the breakfast in addition to their oral hypoglycaemic agents. The patients who could not achieve the target from 12 to 16 weeks after the start of insulin treatment proceeded to twice daily insulin injection before breakfast and dinner. Next, the patients who could not achieve the target from 12 to 16 weeks after the addition of another BIAsp injection proceeded to thrice daily insulin injection before each meal a day. The results of 39 patients were analyzed, and 10.3 % of all patients achieved the target after the start of once daily injection of BIAsp 30, 41.7 % achieved in twice daily injection of BIAsp, and 51.4 % achieved in thrice daily injection of BIAsp. Daily insulin dose at the end of each treatment was 9.3±4.1 U in once daily, 17.4±6.3 U in twice daily, and 28.4±10.4 U in thrice daily. Total body weight increase by 2.0±2.6 kg. The initiation and titration protocol with BIAsp 30 improved glycaemic control, and increased the number of patients with the achievement of glycaemic goals.     

Molecular cloning of prepro-thyrotropin-releasing hormone cDNA from medaka (Oryzias latipes)

The cDNA encoding prepro-thyrotropin-releasing hormone (ppTRH) in a teleost, medaka (Oryzias latipes) was isolated and characterized. The medaka ppTRH cDNA codes for 270 amino acid residues including eight TRH progenitor sequences (-Lys/Arg-Arg-Gln-His-Pro-Gly-Lys/Arg-Arg-). In silico analyses of the medaka genome database predicted that the structure of the medaka ppTRH gene is similar to the ppTRH genes of the other vertebrate species studied to date; consisting of three exons and two introns. Identity of the medaka ppTRH with the other vertebrates is rather low except the sockeye salmon. A molecular phylogenic tree showed that the ppTRH sequences reflected the predicted pattern of species classification. RT-PCR analysis demonstrated ppTRH gene expression in the brain and retina. These results gave some insight into the molecular evolution of ppTRH and physiological functions of TRH in vertebrates.     

Inhibition of cell-to-cell transmission of human T-cell lymphotropic virus type 1 in vitro by carbohydrate-binding agents

Peripheral blood mononuclear cells (PBMCs) from healthy individuals can be infected by human T-lymphotropic virus type 1 (HTLV-1) upon cocultivation of the PBMCs with irradiated HTLV-1-transformed human MT-2 cells. This model system closely mimics HTLV-1 transmission through cell-to-cell contact. Carbohydrate-binding agents (CBAs) such as the α(1,3)/α(1,6)mannose-specific Hippeastrum hybrid agglutinin and the GlcNAc-specific Urtica dioica agglutinin, and also the small, nonpeptidic α(1,2)-mannose-specific antibiotic pradimicin A, were able to efficiently prevent cell-to-cell HTLV-1 transmission at nontoxic concentrations, as evidenced by the lack of appearance of virus-specific mRNA and of the viral protein Tax in the acceptor cells. Consistently, antivirally active doses of CBAs fully prevented HTLV-1-induced stimulation of PBMC growth. The inhibitory effects of CBAs on HTLV-1 transmission were also evident when HTLV-1-infected C5MJ cells were used in place of MT-2 cells as a virus donor cell line. The anti-HTLV-1 properties of the CBAs highlight the importance of the envelope glycans in events underlying HTLV-1 passage from cell to cell and indicate that CBAs should be further investigated for their potential to prevent HTLV-1 infection, including mother-to-child virus transmission by cell-to-cell contact through breast milk feeding.