Antibody-drug conjugates (ADCs) are expected as next therapeutic antibodies. At present, four ADCs have been approved. ADCs consist from three components, antibody, cytotoxic agents, and linker. In this paper, recent advances of ADC developments are described. From view of antibody development, internarization ability and cancer stromal targeting therapy concept are described. For cytotoxic agents, features of representative agents including radio isotopes are described. Linker technology development for homogeneous ADC preparation is also focused. Representative bioorthogonal reaction for ADC preparation is also included.

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Liposome is a vesicle composed of a lipid bilayer and widely used as a drug carrier for injectable formulation of drugs and targeting drug delivery system. On the other hand, because an antibody has a potential to strongly and specifically recognize a targeted molecule, it can be said that utilizing the antibody in DDS achieves effective drug delivery to a targeted site such as tumor tissue and ideal medication. In this review, we describe the outline of antibody-modified liposome for active targeting DDS and introduce our recent research on tumor targeting using the antibody-modified liposomes for cancer chemotherapy.

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Selective tumor targeting of therapeutic agents is a longstanding pharmacological goal to improve a therapeutic index. Most scientists have sought to use active receptor-mediated tumor-targeting systems, however the passive targeting afforded by the enhanced permeability and retention （EPR）effect provides a versatile and non-saturable opportunity for tumor-selective delivery. In this context, collaborating with NanoCarrier Co., Ltd., we succeeded in constructing anti-tissue factor （TF）antibody-conjugated micelles incorporating anticancer drugs. In this review article, Drug Delivery System （DDS）of passive and active targeting is described and immunomicelle possessing both passive and active targeting ability is discussed in more detail.

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Recently, the theory of cancer stem cell (CSC) is gaining increasing attention from researchers and has become an important focus of cancer research. Since the discovery that the marker molecule is over-expressed in a variety of solid tumors, many studies have focused on methods for targeting the hyaluronan receptor CD44. Hyaluronic acid, the primary CD44 binding molecule, has proved a significant factor in developing nanocarriers that demonstrate preferential tumor accumulation and increased cell uptake. Research is frequently conducted to add further functions to nanocarriers targeting CD44. It is expected that more effective drug delivery will be possible by combining with existing technology. In this review, we introduce research approaches from the current literature that take advantage of CD44-targeting ability and describe the possible advantages for each approach. Finally, we describe our recent progress in hyaluronic acid-modified thermoresponsive liposome aiming for CD44-targeting and combined with oncothermia.

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CpG ODN, the ligand for TLR9, is expected to be used as an immune adjuvant for vaccines against cancer and infectious diseases. We have been studying on nanostructured nucleic acids to reveal the relationships among their structural properties, interaction with cells, and adjuvant activity. As results, it was found that MSR1 is involved in the uptake of the nanostructured nucleic acids by TLR9-expressing cells. In addition, we developed several types of nanostructured nucleic acids with diverse structural properties using DNA nanotechnology, and demonstrated that they were useful for delivering CpG ODN to TLR9-expressing cells and for increasing cytokine release from the cells. Then, we developed DNA hydrogels by connecting nanostructured nucleic acids using self-gelatinizable nucleic acid technology. The DNA hydrogels containing CpG ODN can stimulate the innate immune system and have a sustained release property of CpG ODN, so that they are quite useful delivery systems with adjuvant activity for cancer immunotherapy.

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Antibody-drug conjugate (ADC) represents a promising class of drugs with a wider therapeutic index than conventional chemotherapy due to their efficient and selective drug delivery. We have developed a novel ADC technology with a potent DNA topoisomerase I inhibitor exatecan derivative. The major advantages of the technology are high and homogeneous drug to antibody ratio, potent anti-tumor activity with bystander effect, less safety concerns due to the stable linker limiting the release of free drug in the circulation and short systemic half-life of the payload. Using this technology, we generated a new anti-HER2 ADC called DS-8201a. DS-8201a was effective against T-DM1-insensitive patient-derived xenograft (PDX) models with high HER2 expression and also demonstrated anti-tumor efficacy against breast cancer PDX models with low HER2 expression. The results of Phase 1 study suggest that DS-8201a was well tolerated and clearly active in breast cancer patients including T-DM1 refractory patients, trastuzumab treated gastric cancer patients and other HER2 expressing and/or mutated cancer patients. Currently, Phase 2 and Phase 3 trials are on-going across multiple tumor types. We also confirmed the versatility of the technology to different combinations of targets and antibodies and showed importance of this new class of novel topoisomerase I inhibitor-based ADC technology.

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