84 research outputs found
Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire
Idiosyncratic adverse drug reactions are unpredictable, dose independent and
potentially life threatening; this makes them a major factor contributing to
the cost and uncertainty of drug development. Clinical data suggest that many
such reactions involve immune mechanisms, and genetic association studies have
identified strong linkage between drug hypersensitivity reactions to several
drugs and specific HLA alleles. One of the strongest such genetic associations
found has been for the antiviral drug abacavir, which causes severe adverse
reactions exclusively in patients expressing the HLA molecular variant B*57:01.
Abacavir adverse reactions were recently shown to be driven by drug-specific
activation of cytokine-producing, cytotoxic CD8+ T cells that required
HLA-B*57:01 molecules for their function. However, the mechanism by which
abacavir induces this pathologic T cell response remains unclear. Here we show
that abacavir can bind within the F-pocket of the peptide-binding groove of
HLA-B*57:01 thereby altering its specificity. This supports a novel explanation
for HLA-linked idiosyncratic adverse drug reactions; namely that drugs can
alter the repertoire of self-peptides presented to T cells thus causing the
equivalent of an alloreactive T cell response. Indeed, we identified specific
self-peptides that are presented only in the presence of abacavir, and that
were recognized by T cells of hypersensitive patients. The assays we have
established can be applied to test additional compounds with suspected HLA
linked hypersensitivities in vitro. Where successful, these assays could speed
up the discovery and mechanistic understanding of HLA linked hypersensitivities
as well as guide the development of safer drugs
Non-Agonistic Bivalent Antibodies That Promote c-MET Degradation and Inhibit Tumor Growth and Others Specific for Tumor Related c-MET
The c-MET receptor has a function in many human cancers and is a proven therapeutic target. Generating antagonistic or therapeutic monoclonal antibodies (mAbs) targeting c-MET has been difficult because bivalent, intact anti-Met antibodies frequently display agonistic activity, necessitating the use of monovalent antibody fragments for therapy. By using a novel strategy that included immunizing with cells expressing c-MET, we obtained a range of mAbs. These c-MET mAbs were tested for binding specificity and anti-tumor activity using a range of cell-based techniques and in silico modeling. The LMH 80 antibody bound an epitope, contained in the small cysteine-rich domain of c-MET (amino acids 519–561), that was preferentially exposed on the c-MET precursor. Since the c-MET precursor is only expressed on the surface of cancer cells and not normal cells, this antibody is potentially tumor specific. An interesting subset of our antibodies displayed profound activities on c-MET internalization and degradation. LMH 87, an antibody binding the loop connecting strands 3d and 4a of the 7-bladed β-propeller domain of c-MET, displayed no intrinsic agonistic activity but promoted receptor internalization and degradation. LMH 87 inhibited HGF/SF-induced migration of SK-OV-3 ovarian carcinoma cells, the proliferation of A549 lung cancer cells and the growth of human U87MG glioma cells in a mouse xenograft model. These results indicate that c-MET antibodies targeting epitopes controlling receptor internalization and degradation provide new ways of controlling c-MET expression and activity and may enable the therapeutic targeting of c-MET by intact, bivalent antibodies
The discovery of Hepatocyte Growth Factor (HGF) and its significance for cell biology, life sciences and clinical medicine
It has been more than 25 years since HGF was discovered as a mitogen of hepatocytes. HGF is produced by stromal cells, and stimulates epithelial cell proliferation, motility, morphogenesis and angiogenesis in various organs via tyrosine phosphorylation of its receptor, c-Met. In fetal stages, HGF-neutralization, or c-Met gene destruction, leads to hypoplasia of many organs, indicating that HGF signals are essential for organ development. Endogenous HGF is required for self-repair of injured livers, kidneys, lungs and so on. In addition, HGF exerts protective effects on epithelial and non-epithelial organs (including the heart and brain) via anti-apoptotic and anti-inflammatory signals. During organ diseases, plasma HGF levels significantly increased, while anti-HGF antibody infusion accelerated tissue destruction in rodents. Thus, endogenous HGF is required for minimization of diseases, while insufficient production of HGF leads to organ failure. This is the reason why HGF supplementation produces therapeutic outcomes under pathological conditions. Moreover, emerging studies delineated key roles of HGF during tumor metastasis, while HGF-antagonism leads to anti-tumor outcomes. Taken together, HGF-based molecules, including HGF-variants, HGF-fragments and c-Met-binders are available as regenerative or anti-tumor drugs. Molecular analysis of the HGF-c-Met system could provide bridges between basic biology and clinical medicine
Measuring the predictability of life outcomes with a scientific mass collaboration.
How predictable are life trajectories? We investigated this question with a scientific mass collaboration using the common task method; 160 teams built predictive models for six life outcomes using data from the Fragile Families and Child Wellbeing Study, a high-quality birth cohort study. Despite using a rich dataset and applying machine-learning methods optimized for prediction, the best predictions were not very accurate and were only slightly better than those from a simple benchmark model. Within each outcome, prediction error was strongly associated with the family being predicted and weakly associated with the technique used to generate the prediction. Overall, these results suggest practical limits to the predictability of life outcomes in some settings and illustrate the value of mass collaborations in the social sciences
- …