Antibodies as drugs-a Keystone Symposia report.

Therapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to identify antibodies with therapeutic potential as well as methods to improve upon endogenous antibodies and to design antibodies de novo. On April 27-30, 2022, experts in antibody research across academia and industry met for the Keystone symposium "Antibodies as Drugs" to present the state-of-the-art in antibody therapeutics, repertoires and deep learning, bispecific antibodies, and engineering.

Immune repertoire profiling for disease pathobiology.

Lymphocytes consist of highly heterogeneous populations, each expressing a specific cell surface receptor corresponding to a particular antigen. Lymphocytes are both the cause and regulator of various diseases, including autoimmune/allergic diseases, lifestyle diseases, neurodegenerative diseases, and cancers. Recently, immune repertoire sequencing has attracted much attention because it helps obtain global profiles of the immune receptor sequences of infiltrating T and B cells in specimens. Immune repertoire sequencing not only helps deepen our understanding of the molecular mechanisms of immune-related pathology but also assists in discovering novel therapeutic modalities for diseases, thereby shedding colorful light on otherwise tiny monotonous cells when observed under a microscope. In this review article, we introduce and detail the background and methodology of immune repertoire sequencing and summarize recent scientific achievements in association with human diseases. Future perspectives on this genetic technique in the field of histopathological research will also be discussed.

Nucleic acid-triggered tumoral immunity propagates pH-selective therapeutic antibodies through tumor-driven epitope spreading.

Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.

Universal encoding of pan-cancer histology by deep texture representations.

Cancer histological images contain rich biological and clinical information, but quantitative representation can be problematic and has prevented the direct comparison and accumulation of large-scale datasets. Here, we show successful universal encoding of cancer histology by deep texture representations (DTRs) produced by a bilinear convolutional neural network. DTR-based, unsupervised histological profiling, which captures the morphological diversity, is applied to cancer biopsies and reveals relationships between histologic characteristics and the response to immune checkpoint inhibitors (ICIs). Content-based image retrieval based on DTRs enables the quick retrieval of histologically similar images using The Cancer Genome Atlas (TCGA) dataset. Furthermore, via comprehensive comparisons with driver and clinically actionable gene mutations, we successfully predict 309 combinations of genomic features and cancer types from hematoxylin-and-eosin-stained images. With its mounting capabilities on accessible devices, such as smartphones, universal encoding for cancer histology has a strong impact on global equalization for cancer diagnosis and therapies.

Focal adhesion ribonucleoprotein complex proteins are major humoral cancer antigens and targets in autoimmune diseases.

Despite the accumulating evidences of the significance of humoral cancer immunity, its molecular mechanisms have largely remained elusive. Here we show that B-cell repertoire sequencing of 102 clinical gastric cancers and molecular biological analyses unexpectedly reveal that the major humoral cancer antigens are not case-specific neo-antigens but are rather commonly identified as ribonucleoproteins (RNPs) in the focal adhesion complex. These common antigens are shared as autoantigens with multiple autoimmune diseases, suggesting a direct molecular link between cancer- and auto-immunity on the focal adhesion RNP complex. This complex is partially exposed to the outside of cancer cell surfaces, which directly evokes humoral immunity and enables functional bindings of antibodies to cancer cell surfaces in physiological conditions. These findings shed light on humoral cancer immunity in that it commonly targets cellular components fundamental for cytoskeletal integrity and cell movement, pointing to a novel modality of immunotherapy using humoral immunological reactions to cancers.

Extranodal NK/T-cell lymphoma of the nasal cavity developed in a patient with intestinal Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder.

Extranodal NK/T cell lymphoma, nasal type (ENKL) developed in a patient with intestinal Epstein-Barr virus (EBV)-positive T/NK-cell lymphoproliferative disorder (LPD). The patient was a 46-year-old Chinese man who complained of diarrhea and abdominal pain without immune-deficiency. Endoscopy demonstrated ileum ulcers like Crohn's disease, without histological granulomas. His symptoms continued waxing and waning for 3 years until he developed overt lymphoma (ENKL) in the nasal cavity. The ileum lesions exacerbated into a large deep ulcer, and the biopsy specimens from the ileum, including the one 3 years ago, showed infiltration of small lymphocytes containing many EBV-positive T/NK cells without atypia. Thus, the patient illness of intestine was revealed as intestinal EBV-positive T/NK-cell LPD, which might be closely associated with development of ENKL in this patient. In cases of inflammatory bowel disease without typical clinical courses and histological findings, check-up of EBV in the biopsy might help correct diagnosis.