Dimerization of LTβR by LTα<sub>1</sub>β<sub>2</sub>is necessary and sufficient for signal transduction

Sudhamsu, Jawahar; Yin, Jianping; Chiang, Eugene Y.; Starovasnik, Melissa A.; Grogan, Jane L.; Hymowitz, S.G.

doi:10.1073/pnas.1310838110

Cited by 34 publications

(26 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It should be noted that LTα on the surface of immune cells exists as a heterotrimer of LT α1/β2. LTα is also present in a secreted form as homotrimeric LTα3, which acts on TNFR1/2, not LTβr (63). Here, we tested the hypothesis that the activation of FRCs occurs via signaling through the LTα/LTβr pathway.…”

Section: Discussionmentioning

confidence: 99%

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

Maarouf¹,

Uehara²,

Kasinath³

et al. 2018

JCI Insight

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

Maarouf¹,

Uehara²,

Kasinath³

et al. 2018

JCI Insight

Self Cite

View full text Add to dashboard Cite

“…Despite low to moderate sequence homology, all TNFSF members show high structural homology (2,3,. A homotrimer has been observed for all TNFSF members with the exception of dimeric murine GITRL (30) (that likely represents a nonfunctional state) and the heterotrimeric LT (12). The corresponding receptor monomers bind on the outside at the interface between two ligand monomers ( Fig.…”

Section: A Trimeric Ligand Bound To Three Receptors Forms the Basic Umentioning

confidence: 94%

Structural principles of tumor necrosis factor superfamily signaling

2018

View full text Add to dashboard Cite

The tumor necrosis factor (TNF) ligand and receptor superfamilies play an important role in cell proliferation, survival, and death. Stimulating or inhibiting TNF superfamily signaling pathways is expected to have therapeutic benefit for patients with various diseases, including cancer, autoimmunity, and infectious diseases. We review our current understanding of the structure and geometry of TNF superfamily ligands, receptors, and their interactions. A trimeric ligand and three receptors, each binding at the interface of two ligand monomers, form the basic unit of signaling. Clustering of multiple receptor subunits is necessary for efficient signaling. Current reports suggest that the receptors are prearranged on the cell surface in a "nonsignaling," resting state in a large hexagonal structure of antiparallel dimers. Receptor activation requires ligand binding, and cross-linking antibodies can stabilize the receptors, thereby maintaining the active, signaling state. On the other hand, an antagonist antibody that locks receptor arrangement in antiparallel dimers effectively blocks signaling. This model may aid the design of more effective TNF signaling-targeted therapies.

show abstract

“…Production and Characterization of Antibody VariantsCrystal structures of anti-LT␣:LT␣ (Protein Data Bank code 4MXV) (29) and humAb4D5-8:HER2 (Protein Data Bank code 1N8Z) (30) were examined using MacPyMOL (Schrödinger, Inc.). In addition to selection criteria of non-antigen contact and side chain solvent accessibility, high variability in the Kabat database (31) was used to choose sites for substitution.…”

Section: Methodsmentioning

confidence: 99%

Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics

Yadav¹,

Sharma²,

Boswell³

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The pharmacokinetic (PK) behavior of monoclonal antibodies in cynomolgus monkeys (cynos) is generally translatable to that in humans. Unfortunately, about 39% of the antibodies evaluated for PKs in cynos have fast nonspecific (or non-targetmediated) clearance (in-house data). An empirical model relating variable region (Fv) charge and hydrophobicity to cyno nonspecific clearance was developed to gauge the risk an antibody would have for fast nonspecific clearance in the monkey. The purpose of this study was to evaluate the predictability of this empirical model on cyno nonspecific clearance with antibodies specifically engineered to have either high or low Fv charge. These amino acid changes were made in the Fv region of two test antibodies, humAb4D5-8 and anti-lymphotoxin ␣. The humAb4D5-8 has a typical nonspecific clearance in cynos, and by making it more positively charged, the antibody acquires fast nonspecific clearance, and making it less positively charged did not impact its clearance. Anti-lymphotoxin ␣ has fast nonspecific clearance in cynos, and making it more positively charged caused it to clear even faster, whereas making it less positively charged caused it to clear slower and within the typical range. These trends in clearance were also observed in two other preclinical species, mice and rats. The effect of modifying Fv charge on subcutaneous bioavailability was also examined, and in general bioavailability was inversely related to the direction of the Fv charge change. Thus, modifying Fv charge appears to impact antibody PKs, and the changes tended to correlate with those predicted by the empirical model.Hundreds of monoclonal antibody (mAb) therapeutics have been evaluated in clinical trials as potential life-saving therapeutics, yet only about 30 are approved for use in the United States and/or Europe, and they span therapeutic areas such as oncology, ophthalmology, viral infections, and autoimmune disease (1). These therapeutics fail for four main reasons, including lack of efficacy, safety, business, and others (2). As such, there is an effort to conduct appropriate preclinical studies to reduce the chances of failure as much as possible in the clinic. The focus of this paper is on efforts to lower the risk of fast antibody pharmacokinetics.Factors that affect antibody pharmacokinetics (PK) 2 include antibody-specific properties (charge, hydrophobicity, target affinity, FcRn affinity, Fc␥ receptor interactions, and glycosylation) (3), target properties (expression level, turnover rate, and soluble versus membrane-associated) (4, 5), drug administration (dose and route) (3, 6), anti-therapeutic antibody formation (6, 7), off-target/nonspecific binding (8 -12), and disease state (healthy volunteers versus patients) (13). Given the many factors that could affect the PK of therapeutic antibodies, finding a representative preclinical species in which to assess PK is imperative. An in-depth analysis of 23 monoclonal antibodies with linear PK and six with non-linear PK from three preclinical species...

show abstract

Dimerization of LTβR by LTα₁β₂is necessary and sufficient for signal transduction

Cited by 34 publications

References 39 publications

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

Structural principles of tumor necrosis factor superfamily signaling

Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics

Contact Info

Product

Resources

About

Dimerization of LTβR by LTα1β2is necessary and sufficient for signal transduction

Cited by 34 publications

References 39 publications

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

Structural principles of tumor necrosis factor superfamily signaling

Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics

Contact Info

Product

Resources

About

Dimerization of LTβR by LTα₁β₂is necessary and sufficient for signal transduction