The CCR5 receptor acts as an alloantigen in CCR5Δ32 homozygous individuals: Identification of chemokineand HIV-1-blocking human antibodies

The chemokine receptor CCR5 is the major coreceptor for infection by macrophage-tropic R5 HIV-1. A 32-bp deletion in the gene coding for CCR5 (CCR5Δ32) occurs with a frequency of 10% in the Caucasian population and results in a receptor protein that is truncated and not expressed at the cell surface. CCR5Δ32 homozygous individuals are apparently normal but resistant to infection with R5 HIV-1. In two individuals homozygous for CCR5Δ32, who had been repeatedly exposed to CCR5-expressing blood cells through sexual activity, we have identified antibodies to CCR5 that bound specifically to the surface of CCR5-expressing cell lines. Serum from these individuals, in contrast to serum from CCR5(+/+) individuals, competed with radiolabeled RANTES for binding to the CCR5 receptor and inhibited infection of peripheral blood mononuclear cells with R5, but not X4, primary isolates of HIV-1. The identified human antibodies to CCR5 define an alloantigen that may cause allograft rejection in a mismatch situation even in individuals with no history of blood transfusions or i.v. drug abuse

Potassium isotope composition of Mars reveals a mechanism of planetary volatile retention

The abundances of water and highly to moderately volatile elements in planets are considered critical to mantle convection, surface evolution processes, and habitability. From the first flyby space probes to the more recent “Perseverance” and “Tianwen-1” missions, “follow the water,” and, more broadly, “volatiles,” has been one of the key themes of martian exploration. Ratios of volatiles relative to refractory elements (e.g., K/Th, Rb/Sr) are consistent with a higher volatile content for Mars than for Earth, despite the contrasting present-day surface conditions of those bodies. This study presents K isotope data from a spectrum of martian lithologies as an isotopic tracer for comparing the inventories of highly and moderately volatile elements and compounds of planetary bodies. Here, we show that meteorites from Mars have systematically heavier K isotopic compositions than the bulk silicate Earth, implying a greater loss of K from Mars than from Earth. The average “bulk silicate” δ(41)K values of Earth, Moon, Mars, and the asteroid 4-Vesta correlate with surface gravity, the Mn/Na “volatility” ratio, and most notably, bulk planet H(2)O abundance. These relationships indicate that planetary volatile abundances result from variable volatile loss during accretionary growth in which larger mass bodies preferentially retain volatile elements over lower mass objects. There is likely a threshold on the size requirements of rocky (exo)planets to retain enough H(2)O to enable habitability and plate tectonics, with mass exceeding that of Mars

Rational identification of an optimal antibody mixture for targeting the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) is frequently dysregulated in human malignancies and a validated target for cancer therapy. Two monoclonal anti-EGFR antibodies (cetuximab and panitumumab) are approved for clinical use. However, the percentage of patients responding to treatment is low and many patients experiencing an initial response eventually relapse. Thus, the need for more efficacious treatments remains. Previous studies have reported that mixtures of antibodies targeting multiple distinct epitopes are more effective than single mAbs at inhibiting growth of human cancer cells in vitro and in vivo. The current work describes the rational approach that led to discovery and selection of a novel anti-EGFR antibody mixture Sym004, which is currently in Phase 2 clinical testing. Twenty-four selected anti-EGFR antibodies were systematically tested in dual and triple mixtures for their ability to inhibit cancer cells in vitro and tumor growth in vivo. The results show that targeting EGFR dependent cancer cells with mixtures of antibodies is superior at inhibiting their growth both in vitro and in vivo. In particular, antibody mixtures targeting non-overlapping epitopes on domain III are efficient and indeed Sym004 is composed of two monoclonal antibodies targeting this domain. The superior growth inhibitory activity of mixtures correlated with their ability to induce efficient EGFR degradation

Hunting for the elusive target antigen in gestational alloimmune liver disease (GALD)

The prevailing concept is that gestational alloimmune liver disease (GALD) is caused by maternal antibodies targeting a currently unknown antigen on the liver of the fetus. This leads to deposition of complement on the fetal hepatocytes and death of the fetal hepatocytes and extensive liver injury. In many cases, the newborn dies. In subsequent pregnancies early treatment of the woman with intravenous immunoglobulin can be instituted, and the prognosis for the fetus will be excellent. Without treatment the prognosis can be severe. Crucial improvements of diagnosis require identification of the target antigen. For this identification, this work was based on two hypotheses: 1. The GALD antigen is exclusively expressed in the fetal liver during normal fetal life in all pregnancies; 2. The GALD antigen is an alloantigen expressed in the fetal liver with the woman being homozygous for the minor allele and the father being, most frequently, homozygous for the major allele. We used three different experimental approaches to identify the liver target antigen of maternal antibodies from women who had given birth to a baby with the clinical GALD diagnosis: 1. Immunoprecipitation of antigens from either a human liver cell line or human fetal livers by immunoprecipitation with maternal antibodies followed by mass spectrometry analysis of captured antigens; 2. Construction of a cDNA expression library from human fetal liver mRNA and screening about 1.3 million recombinants in Escherichia coli using antibodies from mothers of babies diagnosed with GALD; 3. Exome/genome sequencing of DNA from 26 presumably unrelated women who had previously given birth to a child with GALD with husband controls and supplementary HLA typing. In conclusion, using the three experimental approaches we did not identify the GALD target antigen and the exome/genome sequencing results did not support the hypothesis that the GALD antigen is an alloantigen, but the results do not yield basis for excluding that the antigen is exclusively expressed during fetal life., which is the hypothesis we favor