The DXd ADC technology is an innovative platform that combines a DNA topoisomerase I（TOP1） inhibitor, specifically the proprietary exatecan derivative（DXd）, with a cathepsin-cleavable peptide linker, achieving a high drug-to-antibody ratio and enhanced stability in the blood circulation. The first DXd ADC, trastuzumab deruxtecan（T-DXd）, was initially approved for HER2-positive breast cancer and later expanded its indications to include HER2-low breast cancer and HER2-positive solid tumors across multiple cancer types, offering new treatment options in patients with unmet medical needs. Following T-DXd, the use of TOP1 inhibitors in ADCs has become a growing trend, and the DXd ADC platform is currently advancing clinical trials for five new ADCs. New generation ADCs are now exploring the use of more potent payloads or alternative mechanisms of action to overcome the drug resistance, etc. These novel technologies are expected to bring about new paradigm shift in cancer treatment, providing new therapeutic options for patients.

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Conventional antibodies bind to a single epitope or antigen（Target）. On the other hand, bispecific antibodies bind to two targets. In drug development, Modeling & Simulation（M&S） has been implemented the development strategies. M&S was using as an internal decision-making tool in the company, and information was rarely disclosed. Recently, some articles have reported “setting initial dose, exposure-response, to avoid adverse event” for bispecific antibody using M&S. In this article, introduce two types of development product, focusing on the purpose of M&S and how to utilize existing data.

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Effective treatments remain insufficient for conditions such as cancer, autoimmune diseases, infections, and neurological disorders, resulting in numerous unmet medical needs that require new drug development. On the other hand, antibody therapeutics, known as “magic bullets” for their ability to identify and act on target cells or proteins precisely, have contributed to overcoming these challenges. Additionally, advancements are being made in next-generation antibody therapeutics, including Antibody-drug conjugates（ADCs）, Radioimmunotherapy, and Bispecific antibodies（including T cell engagers） that can recognize two targets simultaneously. These developments are expected to provide new modalities for areas with low treatment satisfaction and efficacy, improving future patient quality of life（QOL）. therapeutic effectiveness was previously low, offering hope for improved quality of life.

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Oligonucleotide therapeutics have gained considerable attention as a new class of molecular targeted drugs. The major issues in the therapeutic use of oligonucleotides are the rapid degradation of administered oligonucleotides and their low delivery efficiency to target tissues and cells. Although nuclease-resistant oligonucleotides with high potency have been developed, the current oligonucleotide delivery is limited to the liver, compromising the therapeutic application of oligonucleotides. To explore the oligonucleotide delivery beyond the liver, we have developed a series of nano-assemblies, so-called polyion complexes（PICs）, from anionic oligonucleotides and cationic polymers. Fine-tuning of the polymer/oligonucleotide structures provides a variety of PIC structures. For instance, a Y-shaped block copolymer comprising branched poly（ethylene glycol） （PEG） and polylysine（PLys） can form a PIC containing a single oligonucleotide molecule, termed unit PIC（uPIC）. Owing to both prolonged blood circulation and relatively smaller size（〜18 nm in diameter）, the uPIC successfully delivered the oligonucleotide payloads into pancreatic and brain tumor models. As for other PICs, micellar PICs（mPICs） can be obtained by mixing antisense oligonucleotides（ASOs） with linear block copolymers comprising PEG and PLys. Because the core of the mPIC is surrounded by PEG shell, ligand conjugation to the distal end of PEG can provide ligand-decorated mPICs. We constructed glucose-decorated mPICs（Glc-mPICs） for glucose transporter 1（GLUT1）-mediated ASO delivery to the brain. Indeed, Glc-mPIC showed enhanced cellular uptake by specific interaction with GLUT1. Furthermore, systemically administered Glc-mPIC efficiently accumulated in the brain tissue and exhibited significant knockdown of a target gene. We also successfully developed vesicular PICs（vPICs） containing oligonucleotides in the vesicular membrane. Optimization of the cationic functional group in the block copolymer provided stable vPICs even under physiological conditions. To investigate the therapeutic potential of this vPIC, we incorporated an effector enzyme, i.e., RNase H, in the aqueous cavity of the vPIC. Encapsulation of RNase H into the vPIC allowed the simultaneous delivery of RNase H and oligonucleotide to the target cells, leading to a cooperative gene knockdown effect. Overall, our approach can provide a promising nanoplatform for oligonucleotide delivery to intractable tumors and non-cancerous brain.

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Dye molecules such as fluorescent dyes and photosensitizers have been utilized for pathological diagnosis and medical treatment on life science and clinical medicine. For the fluorescent visualization of pathological sites such as tumors inside bodies, the fluorescent dyes need to be accumulated into the pathological site. The photoirradiation to the photosensitizers accumulated in tumors induces the cell death for cancer treatment. The drug delivery system, which regulates the selective and efficient delivery of these dyes to the pathological site is important for not only the live-cell imaging but also the whole-body imaging. In addition, the regulation of the fluorescence intensity and the photosensitizing ability of these dyes has been attempted by precisely designing their molecular structure. In this review, we introduce the recent progress of fluorescent probes and photosensitizers, and discuss the future progress in this research area.

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Theranostics is an innovative medical technology that integrates both therapeutic and diagnostic capabilities, allowing seamless transition from imaging diagnosis to radioisotope therapy by altering the radionuclide label on the same compound. This approach enables not only the quantitative assessment of target molecule expression in diagnostic imaging but also the prediction of therapeutic efficacy. In the drug discovery process, theranostics provides insights into the biodistribution of diagnostic agents, facilitating the optimization of therapeutic agents. This optimization can reduce physiological accumulation in normal organs, thereby minimizing potential side effects. Japan has taken a leading role globally in developing and clinically applying theranostics using astatine（²¹¹At）, a radionuclide that can be produced using cyclotrons. The advancement of ²¹¹At-based drug development offers significant potential for future theranostic applications, with expectations for expanded clinical use and therapeutic innovation.

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Efforts to reduce costs and improve efficiency in drug discovery have driven the rapid integration of computational technologies into the pharmaceutical field. In particular, the quantitative advances in computational resources and data availability in recent years have enabled transformative innovations based on deep learning, fueling widespread discussions about the potential of AI under the term “AI drug discovery.” AlphaFold2, which has revolutionized the accuracy of protein tertiary structure prediction, serves as a landmark example of AI technology in drug discovery. Its applications span diverse areas, including peptide and antibody design, significantly expediting the identification and optimization of drug candidate molecules. Furthermore, advancements in language model technologies, originally pioneered in natural language processing, have facilitated sophisticated information representation through chemical and protein language models. These models support highly accurate predictions across a range of modalities and outcomes, offering unprecedented utility in the drug discovery process. The introduction of AlphaFold3 has further advanced the precision of protein-drug complex structure prediction, unlocking new opportunities for molecular design and therapeutic innovation. This review highlights the latest advancements in molecular design powered by AI technologies and examines their contributions to the increasingly complex and diverse landscape of modern drug discovery, supported by illustrative examples.

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NexoBrid^Ⓡ is a topical formulation for eschar removal, a botanical biological drug product that consists of a concentrate of proteolytic enzymes enriched in bromelain sourced from the botanical raw material（BRM）, stems of Ananas comosus（L.） Merr（pineapple plant）, as the active pharmaceutical ingredient（API）. It is applied by mixing a lyophilized product containing the API with hydrating vehicle gel before use. Since the proteolytic action of the active ingredient can selectively degrade and remove thermally injured burn eschar, it is expected to contribute to medical care as an alternative to the conventional excisional, surgical debridement. MediWound, an Israeli pharmaceutical company, conducted clinical studies of NexoBrid abroad, and NexoBrid has been approved in more than 40 countries, including Europe and the United States. In Japan, the efficacy and safety of NexoBrid was confirmed in a phase III study in adults and children with burns, and the drug was approved in December 2022. This article presents the history of development, characteristics, and the results of clinical studies of NexoBrid.

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