Exo-Cleavable Linkers: Enhanced Stability and Therapeutic Efficacy in Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) combine cytotoxic payloads with monoclonal antibodies through chemical linkers. Finding linkers that both enhance circulatory stability and enable effective tumor payload release remains a challenge. The conventional valine-citrulline (Val-Cit) linker is associated with several inherent drawbacks, including hydrophobicity-induced aggregation, a limited drug-antibody ratio (DAR), and premature payload release.

A Novel Index Including Age, Sex, hTERT, and Methylated RUNX3 Is Useful for Diagnosing Early Gastric Cancer.

Introduction: As the incidence of gastric cancer (GC) is increasing in East Asia including Japan, a simple blood test for early GC is needed as an alternative to upper gastrointestinal (UGI) endoscopy. We performed this study to address this issue.

Methods: We collected serum samples from 319 participants comprising 225 healthy subjects without GC (control group) and 94 patients with early GC (early GC group).

A case of asymptomatic infection of Ascaris suum identified by PCR-restriction fragment length polymorphism and DNA sequence analysis.

Human ascariasis is a soil-transmitted helminthiasis and remains a neglected tropical disease. Ascaris suum has the potential to cause cross-infections between humans and pigs. In this study, we present a rare case of a patient with asymptomatic infection by Ascaris suum.

Far-Ultraviolet Light at 222 nm Affects Membrane Integrity in Monolayered DLD1 Colon Cancer Cells.

222 nm far-ultraviolet (F-UV) light has a bactericidal effect similar to deep-ultraviolet (D-UV) light of about a 260 nm wavelength. The cytotoxic effect of 222 nm F-UV has not been fully investigated. DLD-1 cells were cultured in a monolayer and irradiated with 222 nm F-UV or 254 nm D-UV.

Far-ultraviolet irradiation at 222 nm destroys and sterilizes the biofilms formed by periodontitis pathogens.

Background: Periodontal disease is the leading cause of tooth loss, and an association between periodontal disease and non-oral systemic diseases has been shown. Formation of biofilm by periodontal pathogens such as Fusobacterium nucleatum, Porphyromonas gingivalis, and Streptococcus mutans and their resistance to antimicrobial agents are at the root of persistent and chronic bacterial infections.

Methods: The bactericidal effect of far-ultraviolet (F-UV) light irradiation at 222 nm on periodontal bacteria was assessed qualitatively and quantitatively.

AJICAP-M: Traceless Affinity Peptide Mediated Conjugation Technology for Site-Selective Antibody-Drug Conjugate Synthesis.

A traceless site-selective conjugation method, "AJICAP-M", was developed for native antibodies at sites using Fc-affinity peptides, focusing on Lys248 or Lys288. It produces antibody-drug conjugates (ADCs) with consistent drug-to-antibody ratios, enhanced stability, and simplified manufacturing. Comparative in vivo assessment demonstrated AJICAP-M's superior stability over traditional ADCs.

Biological Evaluation of Antibody-Drug Conjugates Produced by Tag-Free Lipoate Ligase A Modification.

The concept of tag-free protein modification has attracted considerable interest in chemical biology because of its flexible and straightforward reaction process. In 2021, a groundbreaking approach using lipoate ligase A (LplA) for tag-free enzymatic modification of antibodies was unveiled, demonstrating its potential for the generation of precise antibody conjugates. In this study, to further explore LplA-mediated antibody-drug conjugate (ADC) synthesis, we performed initial biological evaluations of ADCs synthesized using LplA.

Bispecific Antibodies Produced via Chemical Site-Specific Conjugation Technology: AJICAP Second-Generation.

Bispecific antibodies (BisAbs) are biotherapeutics that amalgamate the specificities of two distinct antibodies into one molecule, however, their engineering requires genetic modification and remains time-consuming. Therefore, we used AJICAP second-generation technology, which drives the production of site-specific conjugation without genetic modification requirements, to generate BisAbs. Using haloketone chemistry as an alternative to maleimide chemistry, we successfully produced site-specific antibody conjugates.

Novel formats of antibody conjugates: recent advances in payload diversity, conjugation, and linker chemistry.

Introduction: In the field of bioconjugates, the focus on antibody - drug conjugates (ADCs) with novel payloads beyond the traditional categories of potent cytotoxic agents is increasing. These innovative ADCs exhibit various molecular formats, ranging from small-molecule payloads, such as immune agonists and proteolytic agents, to macromolecular payloads, such as oligonucleotides and proteins.

Areas Covered: This review offers an in-depth exploration of unconventional strategies for designing conjugates with novel mechanisms of action and notable examples of approaches that show promising prospects.

AJICAP Second Generation: Improved Chemical Site-Specific Conjugation Technology for Antibody-Drug Conjugate Production.

The site-directed chemical conjugation of antibodies remains an area of great interest and active efforts within the antibody-drug conjugate (ADC) community. We previously reported a unique site modification using a class of immunoglobulin-G (IgG) Fc-affinity reagents to establish a versatile, streamlined, and site-selective conjugation of native antibodies to enhance the therapeutic index of the resultant ADCs. This methodology, termed "AJICAP", successfully modified Lys248 of native antibodies to produce site-specific ADC with a wider therapeutic index than the Food and Drug Administration-approved ADC, Kadcyla.

MC180295 Inhibited Epstein-Barr Virus-Associated Gastric Carcinoma Cell Growth by Suppressing DNA Repair and the Cell Cycle.

DNA methylation of both viral and host DNA is one of the major mechanisms involved in the development of Epstein-Barr virus-associated gastric carcinoma (EBVaGC); thus, epigenetic treatment using demethylating agents would seem to be promising. We have verified the effect of MC180295, which was discovered by screening for demethylating agents. MC180295 inhibited cell growth of the EBVaGC cell lines YCCEL1 and SNU719 in a dose-dependent manner.

Biological Evaluation of Maytansinoid-Based Site-Specific Antibody-Drug Conjugate Produced by Fully Chemical Conjugation Approach: AJICAP®.

Background: Trastuzumab-emtansine (T-DM1, commercial name: Kadcyla) is well-known antibody-drug conjugate (ADC) and was first approved for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. This molecular format consisting of trastuzumab and maytansinoid payload (emtansine) is very simple, however, T-DM1 has wide heterogeneity due to non-specific conjugation, lowering its therapeutic index (TI).

Methods: To overcome this issue during the chemical modification of the random conjugation approach to generate T-DM1, we developed a novel chemical conjugation technology termed "AJICAP®" for modification of antibodies in site-specific manner by IgG Fc-affinity peptide based reagents.

The bactericidal effect of far-UVC on ESBL-producing Escherichia coli.

Because extended-spectrum beta-lactamase (ESBL) infections can cause life-threatening disease and effective treatments need to be developed, we examined the bactericidal effect of far-ultraviolet C (far-UVC) light therapy on ESBL-producing Escherichia coli (E. coli). The bactericidal effect on 2 types of ESBL-producing E.

Chemical Site-Specific Conjugation Platform to Improve the Pharmacokinetics and Therapeutic Index of Antibody-Drug Conjugates.

To overcome a lack of selectivity during the chemical modification of native non-engineered antibodies, we have developed a technology platform termed "AJICAP" for the site-specific chemical conjugation of antibodies through the use of a class of IgG Fc-affinity reagents. To date, a limited number of antibody-drug conjugates (ADCs) have been synthesized via this approach, and no toxicological study was reported. Herein, we describe the compatibility and robustness of AJICAP technology, which enabled the synthesis of a wide variety of ADCs.

In-situ Reverse Phased HPLC Analysis of Intact Antibody-Drug Conjugates.

The field of oncology has recently seen an exponential growth in antibody-drug conjugates (ADCs) as a biopharmaceutical class with seven ADCs being launched onto the market in the last ten years. Despite the increase in the industrial research and development of these compounds, their structural complexity and heterogeneity continue to present various challenges regarding their analysis including reaction monitoring. Robust and simple reaction monitoring analysis are in demand in the view of at-line in-process monitoring, and can instill control, confidence and reliability in the ADC manufacturing process.

Physical characteristics comparison between maytansinoid-based and auristatin-based antibody-drug conjugates.

Aim: Direct analytical comparison of two major drug-linkers in the antibody-drug conjugate (ADC) field was conducted.

Methods: Four different analytical methods [AlogP calculation, reverse phase (RP) high-performance liquid chromatography (HPLC; RP-HPLC), size exclusion chromatography HPLC (SEC-HPLC), and differential scanning calorimetry (DSC)] were tested for this comparison.

Results: Maytansinoid-based ADCs showed less hydrophobicity than auristatin-based ADCs.

Intra-abdominal desmoid tumor mimicking local recurrence of renal cell carcinoma after laparoscopic partial nephrectomy.

A 64-year-old man had an intra-abdominal mass that was detected in a follow-up examination after laparoscopic partial nephrectomy for renal cell carcinoma (RCC). CT showed an enhanced mass of 2.5-cm diameter near the right kidney, where partial nephrectomy had been performed.

Facile and Efficient Chemoenzymatic Semisynthesis of Fc-Fusion Compounds for Half-Life Extension of Pharmaceutical Components.

The formation of Fc-fusions, in which biologically active molecules and the Fc fragment of antibodies are linked to each other, is one of the most efficient and successful half-life extension technologies to be developed and applied to peptide and protein pharmaceuticals thus far. Fc-fusion compounds are generally produced by recombinant methods. However, these cannot be applied to artificial middle molecules, such as peptides with non-natural amino acids, unnatural cyclic peptides, or pharmaceutical oligonucleotides.

Male squirting: Analysis of one case using color Doppler ultrasonography.

Introduction: There is no scientific evidence for the mechanism of male squirting, although the term is common in mass media. Here, we describe the first recording of male squirting using color Doppler ultrasonography.

Case Presentation: We recruited a 25-year-old male volunteer who was able to have male squirting.

Practical application of color Doppler ultrasonography in patients with ejaculatory dysfunction.

We describe two cases in which dynamic analysis of ejaculation using color Doppler ultrasonography was useful in diagnosis of ejaculatory dysfunction and planning of therapy. The first patient was a 32-year-old man with a diagnosis of retrograde ejaculation. A bladder neck collagen injection was carried out, as the main cause was thought to be the bladder neck remaining open during ejaculation.

Comparison of Two Different α1-Adrenoceptor Antagonists, Tamsulosin and Silodosin, in the Treatment of Male Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: A Prospective Randomized Crossover Study.

Objectives: We assessed the efficacy and safety of two α1-adrenoceptor antagonists, tamsulosin and silodosin, in the treatment of male lower urinary tract symptoms.

Methods: Men aged 50 years or older who had a total International Prostate Symptom Score (IPSS) of 8 or higher were enrolled in this study. Forty-six patients were randomized into two groups.

Retroperitoneoscopic nephrectomy for treatment of a case of left single ectopic ureter accompanied by dysplastic kidney.

We report the case of a 7-year-old girl with a single ectopic ureter who was treated with retroperitoneoscopic nephrectomy for a chief complaint of urinary incontinence. Preoperative CT showed a contrasted dysplastic kidney of 1cm in the renal fossa and a left ureteral opening into the vagina. Retroperitoneoscopic left nephrectomy was conducted with opening of the lateroconal fascia to enable identification of the dysplastic kidney.

Salvage high-dose-rate brachytherapy for local prostate cancer recurrence after radiotherapy - preliminary results.

Objective: To assess the preliminary clinical results of salvage high-dose-rate brachytherapy (HDR-BT) applied in cases of suspected local recurrence or of residual tumour after radiotherapy.

Patients And Methods: The subjects were 11 patients who met the above conditions and underwent salvage HDR-BT between December 2006 and January 2009. The T stage at the initial treatment was T1c in three patients, T2 in three patients and T3 in five patients.

Effects of three types of alpha-1 adrenoceptor blocker on lower urinary tract symptoms and sexual function in males with benign prostatic hyperplasia.

Objectives: The aim of the present study was to explore the effects of three different types of alpha-1 adrenoceptor blockers (α1-blocker) on lower urinary tract symptoms (LUTS), erectile dysfunction (ED) and ejaculatory dysfunction (EjD) in patients with benign prostatic hyperplasia.

Methods: A total of 136 male LUTS patients aged 50-80 years with International Prostate Symptom Score (IPSS) ≥8 were enrolled. They were divided into three groups.