Johns Hopkins University

Duke University

Remd Biotherapeutics, Inc.

Amgen Inc.

Other

Hai Yan

Bert Vogelstein

Kenneth W Kinzler

Darell D Bigner

Nickolas Papadopoulos

Victor E Velculescu

Gregory J Riggins

Sian Jones

Rebecca J Leary

Xiaosong Zhang

Chien-Tsun Kuan

D Williams Parsons

Jimmy Cheng-Ho Lin

Philipp Angenendt

Giovanni Parmigiani

Rachel Karchin

Frank J Calzone

Chetan Bettegowda

Yuchen Jiao

Thomas Charles Boone

Devin Dressman

John Zhang

Zachary James Reitman

Jim Shi

Shaw-Fen Sylvia Hu

Luis Diaz

Ralph Hruban

Richard A Lindberg

Nishant Agrawal

Patrick J Killela

Alan Meeker

Bill H Diplas

Roger McLendon

Meng Li

John Howard Sampson

Patrick Y Lu

Bryan Daehahn Choi

Genglin Jin

Donald Williams Parsons

Christopher Gentry Duncan

Nicholas Papadopoulos

Jeong Oh

Yiping He

Rui Yang

Landon Hansen

Zachary J Reitman

Williams Parsons

Kenneth Kinzler

Nickolas Papadapoulos

The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTp-IDHglioblastomas, did not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. The genetic landscape of TERTp-IDHglioblastoma includes tumors that have chromosomal rearrangements upstream of TERT. These rearrangements define a novel molecular subgroup of glioblastoma, that is a telomerase-positive subgroup driven by TERT-structural rearrangements (IDH-TERT).

Directing treatments for glioblastoma based on identifying a somatic structural rearrangement upstream from TERT gene

The present disclosure relates to methods for treating or preventing heart failure using a glucagon receptor blocking agent. In various embodiments, the present disclosure relates to methods for treating or preventing heart failure (e.g., post-myocardial infarction heart failure), diabetic cardiomyopathy heart failure), and lateral ventricular (LV) remodeling, using antigen binding and antagonizing proteins, e.g., fully human antibodies, that specifically bind to and antagonize the function of the human glucagon receptor.

Methods for treating heart failure using glucagon receptor antagonistic antibodies

The present disclosure relates to methods for treating type 1 diabetes (T1D) using a glucagon receptor blocking agent. More specifically, the present disclosure relates to methods for treating T1D using substantially lower doses of insulin supplementation, or even in the absence of insulin supplementation, using antigen binding and antagonizing proteins, e.g., fully human antibodies that specifically bind to and antagonize the function of the human glucagon receptor.

Methods for treating type 1 diabetes using glucagon receptor antagonistic antibodies

This application provides isolated antibodies, and antigen-binding fragments thereof, that specifically bind Programmed Death Ligand-1 (PD-L1). These PD-L1 antibodies, or antigen-binding fragments thereof, have a high affinity for PD-L1, function to inhibit PD-L1, are less immunogenic compared to their unmodified parent antibodies in a given species (e.g., a human), are capable of increasing T-cell proliferation and IL-2 secretion in a mixed lymphocyte reaction, and can be used to treat human diseases (e.g., cancer, infectious diseases, autoimmune diseases, asthma, transplant rejection, and inflammatory disorders).

Immunotherapy using antibodies that bind programmed death ligand-1 (PD-L1)

This application provides, inter alia, antibodies or antigen-binding fragments thereof, targeting CTLA-4 expressed on injured tissues associated with multiple diseases. These anti-CTLA-4 antibodies, or antigen-binding fragments thereof, have a high affinity for CTLA-4 and function to inhibit CTLA-4. The antibodies and antigen-binding fragments are useful for treatment of human diseases, infections, and other conditions.

Cancer treatment using antibodies that bind cytotoxic T-lymphocyte antigen-4 (CTLA-4)

We surveyed 1,230 tumors of 60 different types and found that tumors could be divided into types with low (&#x3c;15%) and high (&#x2265;15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

promoter mutations in gliomas and a subset of tumors

We determined the sequence of ATRX and DAXX in 447 cancers from various sites. We found mutations most commonly in pediatric glioblastoma multiformae (GBM) (11.1%), adult GBM (6.5%), oligodendrogliomas (7.7%) and medulloblastomas (1.5%); and showed that Alternative Lengthening of Telomeres (ALT), a telomerase-independent telomere maintenance mechanism found in cancers that have not activated telomerase, perfectly correlated with somatic mutations of either gene. In contrast, neuroblastomas, and adenocarcinomas of the ovary, breast, and pancreas were negative for mutations in ATRX and DAXX. Alterations in ATRX or DAXX define a specific molecular pathway that is closely associated with an alternative telomere maintenance function in human cancers.

Somatic mutations in ATRX in brain cancer

This application provides isolated antibodies, and antigen-binding fragments thereof, that specifically bind Programmed Death 1 (PD-1). These PD-1 antibodies, or antigen-binding fragments thereof, have a high affinity for PD-1, function to inhibit PD-1, are less immunogenic compared to their unmodified parent antibodies in a given species (e.g., a human), are capable of increasing T-cell proliferation and IL-2 secretion in a mixed lymphocyte reaction, and can be used to treat human diseases (e.g., cancer, infectious diseases, autoimmune diseases, asthma, transplant rejection, and inflammatory disorders).

Immunotherapy using antibodies that bind Programmed Death 1 (PD-1)

This application provides, inter alia, antibodies or antigen-binding fragments thereof, targeting OX40 expressed on injured tissues associated with multiple diseases. These OX40 antibodies, or antigen-binding fragments thereof, have a high affinity for OX40 and function as OX40 agonists or as OX40/OX40L antagonists. The antibodies and antigen-binding fragments are useful for treatment of human diseases, infections, and other conditions.

Anti-OX40 antibodies and methods of activating OX40

We found mutations of the R132 residue of isocitrate dehydrogenase 1 (IDH1) in the majority of grade II and III astrocytomas and oligodendrogliomas as well as in glioblastomas that develop from these lower grade lesions. Those tumors without mutations in IDH1 often had mutations at the analogous R172 residue of the closely related IDH2 gene. These findings have important implications for the pathogenesis and diagnosis of malignant gliomas.

Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma

We found mutations of the R132 residue of isocitrate dehydrogenase 1 (IDH1) in the majority of grade II and III astrocytomas and oligodendrogliomas as well as in gliblastomas that develop from these lower grade lesions. Those tumors without mutations in IDH1 often had mutations at the analogous R172 residue of the closely related IDH2 gene. These findings have important implications for the pathogenesis and diagnosis of malignant gliomas.

The present disclosure relates to methods for treating or preventing obesity and/or nonalcoholic fatty liver diseases (NAFLDs) and/or nonalcoholic steatohepatitis (NASH) using a glucagon receptor blocking agent. In various embodiments, the present disclosure relates to methods for treating or preventing NAFLD/NASH using antigen binding and antagonizing proteins, e.g., fully human antibodies, that specifically bind to and antagonize the function of the human glucagon receptor.

Methods for treating obesity and nonalcoholic fatty liver disease or nonalcoholic steatohepatitis using glucagon receptor antagonistic antibodies

Tert promoter mutations in gliomas and a subset of tumors

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Chapel Hill, NC, United States of America

Hai Yan