NK cell detachment from target cells is regulated by successful cytotoxicity and influences cytokine production

Natural killer(NK)cells participate in early immune defenses against pathogens and tumors and play a major role as immune effector and regulatory cells.The NK cell-mediated elimination of an infected or cancerous cell is a highly regulated process that requires the formation of a cell contact,the establishment of an immunological synapse and the polarization and release of lytic granules.Additionally,the detachment of NK cells from target cells is important for NK cells to bind and kill other cells in a process called serial killing.However,very little is known about this detachment process.Here,we show that NK detachment is directly connected to the successful killing of a target cell.The inhibition of killing due to reduced NK cell cytotoxicity or increased target cell resistance results in defective detachment and prolonged contact times.This effect leads to sustained Ca^(2+) flux in NK cells and the hypersecretion of proinflammatory cytokines.Linking defective cytotoxicity with enhanced cytokine secretion via reduced detachment may explain inflammatory pathologies in several diseases.

Monoclonal antibody pharmacogenomics in cancer treatment

Conventionally, in the pharmacokinetic/pharmacodynamic analysis of small molecule compounds such as cytotoxic anticancer drugs, polymorphism analysis of genes related to absorption, distribution, metabolism, and excretion has been performed in addition to the analyses of blood concentrations of drugs. Such pharmacogenetic factors play an important role in predicting therapeutic effects and adverse events and in the proper use of drugs. With the recent launch of immune checkpoint inhibitors (ICIs) and the rapid development of antibody-drug conjugates (ADCs) currently underway, there is no doubt that antibody drugs, which are large molecule compounds, will become key drugs in anticancer drug treatment. However, the pharmacokinetic and pharmacodynamic analysis of antibody drugs is still not sufficient, and further elucidation of factors and mechanisms affecting their dynamics in the human body is necessary. Moreover, the pharmacogenomic factors of antibody drugs have not yet been fully studied. There are many factors that should be clarified, such as factors that regulate the host immune response in ICI therapy and the effects of ATP-binding cassette transporter and cytochrome P450 on the payload of ADCs. This review provides an outline of antibody drugs in cancer treatment and summarizes the pharmacogenomic factors of antibody drugs known to date.

IgG Fc engineering to modulate antiboc affector functions

Therapeutic monoclonal antibodies are among the most effective biotherapeutics to date. An important aspect of antibodies is their ability to bind antigen while at the same time recruit immune effector functions. The majority of approved recombinant monoclonal antibody therapies are of the human IgG1 subclass, which can engage both humoral and cellular components of the immune system. The wealth of information generated about antibodies has afforded investigators the ability to molecularly engineer antibodies to modulate effector functions. Here, we review various antibody engineering efforts intended to improve efficacy and safety relative to the human IgG isotype. Further, we will discuss pro- posed mechanisms by which engineering approaches led to modified interactions with immune components and provide examples of clinical studies using next generation antibodies.