Lapatinib is a low-molecular-weight agent targeting the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). It is one of the antitumor agents used against advanced breast cancer in human. We intended to apply it against canine mammary gland tumors (cMGTs). To this end, we evaluated the tolerated dosage and the side effects of lapatinib in healthy dogs. In this study, we conducted a dose-escalation toxicity test starting from 30 mg/kg to determine the maximum tolerated dose. Grade 3 toxicity, which was apparent as weight loss, was observed at the dose of 40 mg/kg/day. We then performed a long-term administration test and found that the dose of 35 mg/kg/day was well-tolerated within 7 weeks but caused grade 3 hepatic toxicity by the eighth week. In conclusion, our findings reveal that the dose of 35 mg/kg/day administered for no more than 8 weeks is fairly safe for use in healthy dogs. This dose is higher than the recommended dose for humans; thus, further studies evaluating the effective dose against canine tumors are needed.

With the development of information technology, digital pathology, including image analysis, and automatic diagnosis of pathological tissue, has developed remarkably. It has become possible to recognize and quantify histopathological features using artificial intelligence (AI). We have attempted to analyze and quantify various histopathological findings using image processing software. In this report, we introduce the latest results of recognition and quantification of various pathological findings in the liver, kidney, and lung using image processing software, including Image-Pro Plus, Tissue Studio, and HALO. HALO is an image analysis platform specialized for the study of pathological tissues, which enables tissue segmentation by using AI. Using HALO, histopathological changes, which are difficult or impossible to analyze with conventional image analysis, could be easily, and accurately analyzed. Quantification of pathological findings by image analysis can contribute to improve objectivity, precision, and persuasiveness of pathological evaluation. Quantification of morphological changes of histopathological findings using digital pathology including AI in robust pathology is a new and innovative evaluation technique. In the future, a versatile and useful tool is expected to enable faster and more efficient pathological evaluation in both non-clinical and clinical fields.

The term “Mi-byo” is increasingly used nowadays like a buzzword since people are afraid of diseases that may eventually fall on themselves with aging. In addition, it is also known that one out of two Japanese has cancer. Thus, it is necessary to identify the marker used to judge the health condition of humans, which is represented by the word “pre-disease”. Pre-disease is a condition in which no special abnormality is found even after undergoing an examination, and a specific illness is not diagnosed, but it cannot be said that the person is healthy. Many studies state that it is likely that it will cause illness if left unchecked. Thus, persons suffering from conditions such as hyperlipidemia, diabetes, and hypertension, can be considered as “undiseased”. However, it is important to develop new biomarkers or tools to quickly find the signs of these diseases and restore them to their original state. Therefore, in this review, I will overview the recent progress of a novel approach to diagnostic and therapeutic needs using small particles named extracellular vesicles (EVs).

Antibody-drug conjugates (ADCs) are considered as next-generation antibody medicine. At present, heterogeneous ADCs are available; however, their safety and efficacy are suboptimal. Homogeneous ADCs offer increased efficacy, reproducibility, and predictability of their pharmacokinetic and pharmacodynamic effects. The presence of N-glycan in the fragment crystallizable (Fc) region affects antibody function and understanding the mechanisms underlying this effect is critical for improvement of antibody therapy. In this mini-review, we described recent progress towards creation of homogeneous glycan-conjugated ADCs. The glycan-conjugated ADCs possess homogeneity in their drug-antibody ratio and structure. In addition, homogeneous glycan-conjugated ADCs exhibit potent cytotoxicity in vitro.

The development of oligonucleotide therapeutics (ONTs) has advanced recently. Various ONTs (e.g., antisense oligonucleotides, small-interfering RNA, and microRNA) exert their pharmacological effects via hybridization with mRNA sequences, and they can also bind to unintended mRNA sequences owing to sequence homology. For this reason, the safety of ONTs should be evaluated by judging hybridization-dependent on- and off-target toxicity in preclinical studies. As the off-target toxicity is unique to ONTs, it is difficult to assess their safety with the current guidelines established for small molecules and biotechnology-derived pharmaceuticals; thus, several research groups, such as the Oligonucleotide Safety Working Group in the Drug Information Association (DIA), have proposed concepts for the preclinical safety evaluation of ONTs. Although there are currently no specific International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for ONTs, the ICH S6 guideline states that “the principles outlined in this guidance may also be applicable to oligonucleotide drugs.” Recently, a preclinical safety guideline for ONTs has been developed by a Japanese working group to address the issues associated with the ICH S6. Here, the preclinical safety assessments of mRNA-targeting ONTs are discussed based on this guidance.

Biopharmaceuticals produced from animal cells and raw materials pose a risk of pathogen contamination. Thus, it is essential to pay special attention to contamination with infectious agents, including microbes, mycoplasmas, and viruses, in these products. In particular, viral contamination in cell banks, intermediates, or final products may occasionally be difficult to identify compared to contamination with other pathogens. Stringent viral tests including clearance tests have been conducted over the past ~20 years in accordance with the guideline Q5A. The safety of these products can be confirmed, to a reasonable extent, using various in vitro and in vivo viral tests, retroviral test, and clearance assessments to examine the viral removal and inactivation achieved by the purification process. However, viral detection using the current assays is not always comprehensive and focuses mainly on conceivable adventitious viruses. Thus, viral detection using high throughput sequencing (HTS) technology may improve the viral safety of biopharmaceutical products.

In recent years, gene therapy drugs have finally been approved in Europe, the U.S., and Japan. In parallel with this, advances in genome editing technologies have enabled therapeutic strategies by gene knockout and gene repair, which were difficult with conventional so-called gene addition therapy. Worldwide, over 30 clinical trials of genome editing therapy have already been conducted, and some protocols have shown not only safety but also therapeutic efficacy. In the clinical application of genome editing, in addition to the technical hurdles of conventional gene therapy, there are problems specific to genome editing technology, such as the risk of introducing DNA mutations due to off-target activity of enzymes and the immune response to the artificial nucleases. It is necessary to consider the objective risk and benefit in comparison to existing therapeutic protocols. It is also essential to further develop technologies for therapeutic application in a wider range of diseases.

Genome editing technologies, including clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system, are expected to become a state-of-the-art strategy for human gene therapy. However, there are several new safety issues to be addressed before clinical use. This review article summarizes the current regulatory status of the safety assessment of genome editing for human gene therapy. In addition, with a focus on unintended genome editing by CRISPR/Cas9 system, this review outlines the methods used to detect off-target sites, and introduces a proposed technical guidance on the safety assessment of ex vivo genome-edited cell products that have been developed by the Regulatory Science (RS) research project of the Japan Agency for Medical Research and Development (AMED) for genome editing.

As the drug development landscape becomes more globalized, the trade-off between global and local development pathways has become an increasingly important issue. Trade-offs are observed in a variety of consequences, including the resources and time required for development and the impact on patient health. From a public health perspective, studies suggest that the choice of global development pathways for new drugs by pharmaceutical companies may have a significant impact on drug efficacy and safety in Japan. In particular, the fact that dose-finding or confirmatory Phase III studies in Japan have led to improved post-marketing safety demonstrates the potential value of collecting local evidence. The global vs. local trade-off has been overlooked because we lack the concepts and tools to discuss it rigorously in the current drug evaluation science. We need to build a framework for drug evaluation science for a new generation.