Glycosylation of the Fc region of IgG has a profound impact on the safety and clinical efficacy of therapeutic antibodies. While the biantennary complex-type oligosaccharide attached to Asn297 of the Fc is essential for antibody effector functions, fucose and outer-arm sugars attached to the core heptasaccharide that generate structural heterogeneity (glycoforms) exhibit unique biological activities. Hence, efficient and quantitative glycan analysis techniques have been increasingly important for the development and quality control of therapeutic antibodies, and glycan profiles of the Fc are recognized as critical quality attributes. In the past decade our understanding of the influence of glycosylation on the structure/function of IgG-Fc has grown rapidly through X-ray crystallographic and nuclear magnetic resonance studies, which provides possibilities for the design of novel antibody therapeutics. Furthermore, the chemoenzymatic glycoengineering approach using endoglycosidase-based glycosynthases may facilitate the development of homogeneous IgG glycoforms with desirable functionality as next-generation therapeutic antibodies. Thus, the Fc glycans are fertile ground for the improvement of the safety, functionality, and efficacy of therapeutic IgG antibodies in the era of precision medicine.
Animals ; Antibodies, Monoclonal ; adverse effects ; pharmacokinetics ; therapeutic use ; Glycosylation ; Humans ; Immunoglobulin G ; chemistry ; metabolism ; Protein Engineering ; methods ; Receptors, Fc ; chemistry ; metabolism ; Treatment Outcome

On May 23, 2017, the US Food and Drug Administration (FDA) approved a treatment for cancer patients with positive microsatellite instability-high (MSI-H) markers or mismatch repair deficient (dMMR) markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-1/programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantigen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as "genetic interpreters" or "genetic translators" and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.
Antibodies, Monoclonal, Humanized ; adverse effects ; therapeutic use ; Antineoplastic Agents, Immunological ; adverse effects ; therapeutic use ; Biomarkers, Tumor ; Humans ; Neoplasms ; drug therapy ; Precision Medicine ; Programmed Cell Death 1 Receptor ; antagonists & inhibitors ; Treatment Outcome ; United States

BACKGROUND/AIMS: The relationship between patient survival and biopsy-proven acute rejection (BPAR) in liver transplant recipients with hepatitis C remains unclear. The aims of this study were to compare the characteristics of patients with and without BPAR and to identify risk factors for BPAR. METHODS: We retrospectively reviewed the records of 169 HCV-RNA-positive patients who underwent LT at three centers. RESULTS: BPAR occurred in 39 (23.1%) of the HCV-RNA-positive recipients after LT. The 1-, 3-, and 5-year survival rates were 92.1%, 90.3%, and 88.5%, respectively, in patients without BPAR, and 75.7%, 63.4%, and 58.9% in patients with BPAR (P<0.001). Multivariate analyses showed that BPAR was associated with the non-use of basiliximab and tacrolimus and the use of cyclosporin in LT recipients with HCV RNA-positive. CONCLUSION: The results of the present study suggest that the immunosuppression status of HCV-RNA-positive LT recipients should be carefully determined in order to prevent BPAR and to improve patient survival.
Antibodies, Monoclonal/therapeutic use ; Biopsy ; Cyclosporine/therapeutic use ; Drug Therapy, Combination ; Genotype ; Graft Rejection/mortality/*prevention & control ; Hepacivirus/genetics/isolation & purification ; Hepatitis C/drug therapy/*virology ; Humans ; Immunosuppressive Agents/*therapeutic use ; *Liver Transplantation/adverse effects ; Polymerase Chain Reaction ; RNA, Viral/blood ; Recombinant Fusion Proteins/therapeutic use ; Recurrence ; Retrospective Studies ; Survival Rate ; Tacrolimus/therapeutic use

Adenocarcinoma ; drug therapy ; Antibodies, Monoclonal ; adverse effects ; Drug Resistance, Neoplasm ; Female ; Fever ; chemically induced ; Humans ; Liver Neoplasms ; secondary ; Lung Neoplasms ; drug therapy ; Middle Aged ; Quinazolines ; therapeutic use

The radiologic findings of a single nodule from Pneumocystis jirovecii pneumonia (PJP) have been rarely reported. We described a case of granulomatous PJP manifesting as a solitary pulmonary nodule with a halo sign in a 69-year-old woman with diffuse large B cell lymphoma during chemotherapy. The radiologic appearance of the patient suggested an infectious lesion such as angioinvasive pulmonary aspergillosis or lymphoma involvement of the lung; however, clinical manifestations were not compatible with the diseases. The nodule was confirmed as granulomatous PJP by video-assisted thoracoscopic surgery biopsy.
Aged ; Antibodies, Monoclonal, Murine-Derived/adverse effects/therapeutic use ; Antineoplastic Agents/adverse effects/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ; Biopsy/methods ; Cyclophosphamide/adverse effects/therapeutic use ; Doxorubicin/adverse effects/therapeutic use ; Female ; Humans ; Lymphoma, Large B-Cell, Diffuse/drug therapy/microbiology ; Pneumocystis jirovecii/pathogenicity ; Pneumonia, Pneumocystis/*diagnosis/*radiography ; Positron-Emission Tomography ; Prednisone/adverse effects/therapeutic use ; Solitary Pulmonary Nodule/*microbiology ; Thoracic Surgery, Video-Assisted ; Tomography, X-Ray Computed ; Vincristine/adverse effects/therapeutic use

We report two cases of rituximab (RTX)-induced interstitial pneumonia in two lymphoma patients receiving RTX treatment. Interstitial pneumonia was successfully managed in these two cases after a one-week-long intervention with corresponding treatments without affecting further treatment of the primary disease. RTX-induced interstitial pneumonia is characterized by a latent onset with an unclear pathological mechanism and absence of typical symptoms. High-resolution CT scan can provide valuable evidence for early diagnosis of RTX-induced interstitial pneumonia, which might be attributed partially to an increased susceptibility to P. jirovecii and fungal infection due to prolonged RTX treatment.
Antibodies, Monoclonal, Murine-Derived ; adverse effects ; Disease Susceptibility ; Humans ; Lung Diseases, Interstitial ; chemically induced ; Rituximab ; Tomography, X-Ray Computed

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-alpha blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-alpha blocker naive and 160 TNF-alpha blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-alpha blockers compared to TNF-alpha-blocker-naive patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-alpha blocker users, and 0.45 for TNF-alpha-blocker-naive patients. The adjusted risk ratio of TB in IBD patients receiving TNF-alpha blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-alpha blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-alpha blockers. Treatment with TNF-alpha blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-alpha blocker therapy.
6-Mercaptopurine/adverse effects/analogs & derivatives/therapeutic use ; Adult ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/therapeutic use ; Antibodies, Monoclonal/adverse effects/therapeutic use ; Cohort Studies ; Colitis, Ulcerative/*drug therapy ; Crohn Disease/*drug therapy ; Female ; Humans ; Latent Tuberculosis/chemically induced/diagnosis/*epidemiology ; Male ; Mycobacterium tuberculosis/isolation & purification ; Republic of Korea ; Retrospective Studies ; Tuberculosis, Pulmonary/chemically induced/diagnosis/*epidemiology ; Tumor Necrosis Factor-alpha/*antagonists & inhibitors

The aims of this study were to assess the risk of tuberculosis (TB) and the status of latent tuberculosis infection (LTBI) in Korean patients with inflammatory bowel disease (IBD) receiving tumor necrosis factor (TNF)-alpha blockers. We reviewed medical records of 525 Korean IBD patients (365 TNF-alpha blocker naive and 160 TNF-alpha blocker exposed) between January 2001 and December 2013. The crude incidence of TB was significantly higher in IBD patients receiving TNF-alpha blockers compared to TNF-alpha-blocker-naive patients (3.1% vs. 0.3%, P=0.011). The mean incidence of TB per 1,000 patient-years was 1.84 for the overall IBD population, 4.89 for TNF-alpha blocker users, and 0.45 for TNF-alpha-blocker-naive patients. The adjusted risk ratio of TB in IBD patients receiving TNF-alpha blocker was 11.7 (95% confidence interval, 1.36-101.3). Pulmonary TB was prevalent in patients treated with TNF-alpha blockers (80.0%, 4/5). LTBI was diagnosed in 17 (10.6%) patients, and none of the 17 LTBI patients experienced reactivation of TB during treatment with TNF-alpha blockers. Treatment with TNF-alpha blockers significantly increased the risk of TB in IBD patients in Korea. De novo pulmonary TB infection was more prevalent than reactivation of LTBI, suggesting an urgent need for specific recommendations regarding TB monitoring during TNF-alpha blocker therapy.
6-Mercaptopurine/adverse effects/analogs & derivatives/therapeutic use ; Adult ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/therapeutic use ; Antibodies, Monoclonal/adverse effects/therapeutic use ; Cohort Studies ; Colitis, Ulcerative/*drug therapy ; Crohn Disease/*drug therapy ; Female ; Humans ; Latent Tuberculosis/chemically induced/diagnosis/*epidemiology ; Male ; Mycobacterium tuberculosis/isolation & purification ; Republic of Korea ; Retrospective Studies ; Tuberculosis, Pulmonary/chemically induced/diagnosis/*epidemiology ; Tumor Necrosis Factor-alpha/*antagonists & inhibitors

There is no consensus on whether it is safe to re-administer tumor necrosis factor-alpha (TNFalpha) inhibitors in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) flared after withdrawal of TNFalpha inhibitors due to active tuberculosis (TB). We evaluated the safety of restarting anti-TNFalpha therapy in patients with TNFalpha-associated TB. We used data of 1,012 patients with RA or AS treated with TNFalpha inhibitors at Seoul St. Mary's Hospital between January 2003 and July 2013 to identify patients who developed active TB. Demographic and clinical data including the results of tuberculin skin tests (TST) and interferon-gamma releasing assays (IGRA) were collected. Fifteen patients developed active TB. Five cases were occurred in RA and 10 cases in AS. Nine of 15 patients had a negative TST or IGRA and 6 TST-positive patients had received prophylaxis prior to initiating anti-TNFalpha therapy. All patients discontinued TNFalpha inhibitors with starting the treatment of TB. Eight patients were re-administered TNFalpha inhibitors due to disease flares and promptly improved without recurrence of TB. TNFalpha inhibitors could be safely resumed after starting anti-TB regimen in patients with RA or AS.
Adult ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/therapeutic use ; Antibodies, Monoclonal/adverse effects/therapeutic use ; Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Antirheumatic Agents/adverse effects/therapeutic use ; Arthritis, Rheumatoid/*drug therapy ; Enzyme Inhibitors/adverse effects/therapeutic use ; Female ; Humans ; Hydroxychloroquine/adverse effects/therapeutic use ; Immunoglobulin G/adverse effects/therapeutic use ; Immunosuppressive Agents/adverse effects/*therapeutic use ; Interferon-gamma Release Tests ; Male ; Methotrexate/adverse effects/therapeutic use ; Middle Aged ; Mycobacterium tuberculosis/isolation & purification ; Receptors, Tumor Necrosis Factor/therapeutic use ; Retrospective Studies ; Spondylitis, Ankylosing/*drug therapy ; Tuberculin Test ; Tuberculosis/*chemically induced/microbiology ; Tumor Necrosis Factor-alpha/*antagonists & inhibitors

Febrile neutropenia (FN) is the major toxicity of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen in the treatment of diffuse large B-cell lymphoma (DLBCL). The prediction of neutropenia and FN is mandatory to continue the planned R-CHOP therapy resulting in successful anti-cancer treatment. The clinical features and patterns of neutropenia and FN from 181 DLBCL patients treated with R-CHOP were analyzed retrospectively. Sixty percent (60.2%) of patients experienced at least one episode of grade 4 neutropenia. Among them, 42.2% of episodes progressed to FN. Forty-eight percent (48.8%) of patients with FN was experienced their first FN during the first cycle of R-CHOP. All those patients never experienced FN again during the rest cycles of R-CHOP. Female, higher stage, international prognostic index (IPI), age > or =65 yr, comorbidities, bone marrow involvement, and baseline serum albumin < or =3.5 mg/dL were significant risk factors for FN by univariate analysis. Among these variables, comorbidities (P=0.009), bone marrow involvement (P=0.006), and female gender (P=0.024) were independent risk factors for FN based on multivariate analysis. On observing the patterns of neutropenia and FN, primary prophylaxis of granulocyte colony-stimulating factor (G-CSF) and antibiotics should be considered particularly in female patients, patients with comorbidities, or when there is bone marrow involvement of disease.
Adolescent ; Adult ; Age Factors ; Aged ; Antibodies, Monoclonal, Murine-Derived/adverse effects/*therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use ; Chemotherapy-Induced Febrile Neutropenia/*etiology ; Cyclophosphamide/administration & dosage/adverse effects/therapeutic use ; Demography ; Doxorubicin/administration & dosage/adverse effects/therapeutic use ; Female ; Humans ; Lymphoma, Large B-Cell, Diffuse/*drug therapy ; Male ; Middle Aged ; Neoplasm Staging ; Neutropenia/etiology/pathology ; Prednisone/administration & dosage/adverse effects/therapeutic use ; Retrospective Studies ; Risk Factors ; Sex Factors ; Vincristine/administration & dosage/adverse effects/therapeutic use ; Young Adult